Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups Results From the Randomized CREDENCE Trial

Sources of Funding This study is sponsored by Janssen Research & Development, LLC, which funded the trial. The sponsor was involved in the study design, the writing of the report, and the decision to submit the article for publication. Canagliflozin has been developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation. Acknowledgments The authors thank all participants, investigators, and trial teams for their participation in the trial and the following people for their contributions to the statistical monitoring and analyses and the protocol development, safety monitoring, and operational implementation over the duration of the trial: Maria Ali, Jim Baldassarre, Dainius Balis, William Canovatchel, Jun Chen, Pei-Ling Chu, Trokon Cooke, Jag Craig, Jacki Danyluk, Mehul Desai, Lyndal Hones, Alan Jenkins, Mary Kavalam, Cha-Chi Lo, Xinchao Luo, Gary Meininger, Rich Oh, Rose Qiu, Nicole Schmitt, Danielle Siebenkaess, Roger Simpson, Anna Temu, Payal Thakkar, Michele Wells, and Renata Yong. The Steering Committee designed the study in conjunction with the sponsor. Dr Mahaffey wrote the first draft of the paper, had full access to the study design information, and had final responsibility for the decision to submit for publication. All authors provided input into subsequent drafts and approved the final version for submission. Editorial assistance for manuscript preparation was provided by Alaina Mitsch, PhD, and Kimberly Dittmar, PhD, of MedErgy, and was funded by Janssen Global Services, LLC. All authors reviewed and approved the manuscript.Peer reviewe

Potential Effects of Elimination of the Black Race Coefficient in eGFR Calculations in the CREDENCE Trial

Background and objectives: The effect of including race in the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation on screening, recruitment, and outcomes of clinical trials is unclear. Design, setting, participants, & measurements: The inclusion and outcomes of participants in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, which randomized individuals with type 2 diabetes and CKD to canagliflozin or placebo, were evaluated after calculating eGFR using the 2009 CKD-EPI creatinine equation with and without a race-specific coefficient or the 2021 CKD-EPI creatinine equation. Treatment effects were estimated using proportional hazards models and piecewise linear mixed effects models for eGFR slope. Results: Of 4401 randomized participants, 2931 (67%) were White participants, 224 (5%) were Black participants, 877 (20%) were Asian participants, and 369 (8%) participants were other race. Among randomized participants, recalculation of screening eGFR using the 2009 equation without a race-specific coefficient had no effect on the likelihood of non-Black participants meeting inclusion criteria but would have excluded 22 (10%) randomized Black participants for eGFR<30 ml/min per 1.73 m2. Recalculation with the 2021 equation would have excluded eight (4%) Black participants for low eGFR and one (0.4%) Black participant for eGFR≥90 ml/min per 1.73 m2, whereas 30 (0.7%) and 300 (7%) non-Black participants would have been excluded for low and high eGFR, respectively. A high proportion (eight of 22; 36%) of end points in Black participants occurred in individuals who would have been excluded following recalculation using the race-free 2009 equation but not when recalculated with the 2021 equation (one of eight; 13%). Cardiovascular and kidney treatment effects remained consistent across eGFR categories following recalculation with either equation. Changes in estimated treatment effects on eGFR slope were modest but were qualitatively larger following recalculation using the 2021 equation. However, the effect of canagliflozin on chronic change in eGFR was attenuated by 7% among Black participants and increased 6% in non-Black participants. Conclusions: In the CREDENCE trial, eGFR recalculation without the race-specific coefficient had small but potentially important effects on event rates and the relative proportion of Black participants without substantially changing efficacy estimates

The Canagliflozin and renal endpoints in diabetes with established nephropathy clinical evaluation (CREDENCE) study rationale, design and baseline characteristics

BACKGROUND: People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. METHODS: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin -versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of ∼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate ≥30 to <90 mL/min/1.73 m2, and albuminuria (urinary albumin:creatinine ratio >300 to ≤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. CONCLUSION: CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease

Renal, cardiovascular, and safety outcomes of canagliflozin by baseline kidney function: a secondary analysis of the CREDENCE randomized trial

BACKGROUND: Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR). METHODS: CREDENCE randomly assigned 4401 participants with an eGFR of 30 to 0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin's lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m2, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m2. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (-1.72 versus -4.33 ml/min per 1.73 m2; between-group difference 2.61 ml/min per 1.73 m2). CONCLUSIONS: Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m2. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791

Supplementary Material for: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics

<b><i>Background:</i></b> People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. <b><i>Methods:</i></b> The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin ­versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of ∼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate ≥30 to <90 mL/min/1.73 m², and albuminuria (urinary albumin:creatinine ratio >300 to ≤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. <b><i>Conclusion:</i></b> CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease. <b><i>Trial Registration:</i></b> EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791