The CIs for these estimates were similarly calculated by multiplying both lower and upper CI values (that have been estimated using the technique defined by Altman and Andersen14) by 5. 0.70; 95% CI, 0.55C0.90) and the ones with preserved kidney function (threat proportion, 0.92; 95% CI, 0.79C1.07; heterogeneity = 0.08). Comparative results of all cardiovascular and renal final results had been very similar across eGFR subgroups, with possible heterogeneity suggested only for the outcome of fatal/nonfatal stroke (heterogeneity = 0.01), as were results for almost all safety outcomes. Conclusions: The effects of canagliflozin on cardiovascular and renal outcomes were not altered by baseline level of kidney function in people with type 2 diabetes and a history or high risk of cardiovascular disease down to eGFR levels of 30 mL/min/1.73 m2. Reassessing current limitations on the use of canagliflozin in chronic kidney disease may allow additional individuals to benefit from this therapy. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: “type”:”clinical-trial”,”attrs”:”text”:”NCT01032629″,”term_id”:”NCT01032629″NCT01032629, “type”:”clinical-trial”,”attrs”:”text”:”NCT01989754″,”term_id”:”NCT01989754″NCT01989754. values for heterogeneity across all levels of baseline eGFR were obtained through the likelihood ratio test. For major cardiovascular, renal, and security outcomes, further analyses were performed, investigating effect modification by eGFR as a continuous variable. For security outcomes, on-treatment analysis was performed (with data from participants who experienced a safety end result while they were receiving canagliflozin or placebo, or within 30 days after discontinuation of the drug or placebo). The exception was for amputation and fracture outcomes, where analyses included participants who received at least 1 dose of canagliflozin or placebo and experienced an event at any time during follow-up. Complete risk differences for the primary end result, hospitalization for heart failure, progression to the composite renal end result, and risk of amputation were estimated by subtracting the incidence rates (per 1000 patient-years) of placebo from those of canagliflozin and multiplying by 5 years. The CIs for these estimates were similarly calculated by multiplying both the lower and upper CI values (which were estimated using the method explained by Altman and Andersen14) by 5. The heterogeneity assessments for complete risk differences were performed using a nonlinear mixed-effect model with treatment, subgroup, and treatment-by-subgroup conversation as the covariates. Analyses were performed with SAS software, version 9.2, and SAS Enterprise Guide, version 7.11. Role of the Funding Source The trials were sponsored by Janssen Research & Development, LLC, and were conducted collaboratively by the sponsor, an academic steering committee, and an academic research business, George Clinical. The sponsor was responsible for study oversight and data collection, and experienced a representative around the Steering Committee, which was responsible for study design, data analysis, data interpretation, and writing of this statement. All authors experienced full access to all the data and experienced final responsibility for the decision to submit for publication. Results The CANVAS Program randomized 10 142 participants with a imply follow-up period of 188.2 weeks. At baseline, 2039 (20.1%) participants had CKD (mean age, 68 years; blood pressure, 137/76 mm?Hg; HbA1c, 8.3%; eGFR, 49 mL/min/1.73 m2; median UACR, 22 mg/g), of whom 71.6% had a prior history of cardiovascular disease. This included 554 participants (5.5%) in the eGFR 45 mL/min/1.73 m2 category, among whom 73.3% had a history of cardiovascular disease. Baseline characteristics of participants with eGFR 45, 45 to 60, 60 to 90, and 90 mL/min/1.73 m2 are presented in Table ?Table1.1. In progressively lower categories of eGFR, participants were older and more likely to be female; be white; have a longer period of diabetes; have AC710 established micro- or macrovascular disease; have a history of heart failure, micro- or macroalbuminuria; and be treated with insulin and cardiovascular protective therapies (all heterogeneity 0.0001). In contrast, reductions in body weight (?2.45, ?2.23, ?1.95, and ?2.30 kg) and blood pressure (?3.92, AC710 ?4.06, ?3.66, and ?3.29 mm?Hg) were comparable across the respective eGFR subgroups (heterogeneity = 0.16 and 0.46). The geometric mean ratio of UACR compared to placebo was ?17%, ?17%, ?26%, and ?13% for the same.Relative effects on most cardiovascular and renal outcomes were comparable across eGFR subgroups, with possible heterogeneity suggested only for the outcome of fatal/nonfatal stroke (heterogeneity = 0.01), as were results for almost all safety outcomes. Conclusions: The effects of canagliflozin on cardiovascular and renal outcomes were not altered by baseline level of kidney function in people with type 2 diabetes and a history or high risk of cardiovascular disease down to eGFR levels of 30 mL/min/1.73 m2. baseline, 2039 (20.1%) participants had an eGFR 60 mL/min/1.73 m2, 71.6% of whom experienced a history of cardiovascular disease. The effect of canagliflozin on the primary outcome was comparable in people with chronic kidney disease (hazard ratio, 0.70; 95% CI, 0.55C0.90) and those with preserved kidney function (hazard ratio, 0.92; 95% CI, 0.79C1.07; heterogeneity = 0.08). Relative effects on most cardiovascular and renal outcomes were comparable across eGFR subgroups, with possible heterogeneity suggested only for the outcome of fatal/nonfatal stroke (heterogeneity = 0.01), as were results for almost all safety outcomes. Conclusions: The effects of canagliflozin on cardiovascular and renal outcomes were not altered by baseline level of kidney function in people with type 2 diabetes and a history or high risk of cardiovascular disease down to eGFR levels of 30 mL/min/1.73 m2. Reassessing current limitations on the use of canagliflozin in chronic kidney disease may allow additional individuals to benefit from this therapy. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: “type”:”clinical-trial”,”attrs”:”text”:”NCT01032629″,”term_id”:”NCT01032629″NCT01032629, “type”:”clinical-trial”,”attrs”:”text”:”NCT01989754″,”term_id”:”NCT01989754″NCT01989754. values for heterogeneity across all levels of baseline eGFR were obtained through the likelihood ratio test. For major cardiovascular, renal, and security outcomes, further analyses were performed, investigating effect modification by eGFR as a continuous variable. For security outcomes, on-treatment analysis was performed (with data from participants who experienced a safety end result while they were receiving canagliflozin or placebo, or within 30 days after discontinuation of the drug or placebo). The exception was for amputation and fracture outcomes, where analyses included participants who received at least 1 dose of canagliflozin or placebo and experienced an event at any time during follow-up. Complete risk differences for the primary end result, hospitalization for heart failure, progression to the composite renal end result, and AC710 risk of amputation were estimated by subtracting the incidence rates (per 1000 patient-years) of placebo from those of canagliflozin and multiplying by 5 years. The CIs for these estimates were similarly calculated by multiplying both the lower and upper CI values (which were estimated using the method explained by Altman and Andersen14) by 5. The heterogeneity assessments for complete risk differences were performed using a nonlinear mixed-effect model with treatment, subgroup, and treatment-by-subgroup conversation as AC710 the covariates. Analyses were performed with SAS software, version 9.2, and SAS Enterprise Guide, version 7.11. Role of the Funding Source The trials were sponsored by Janssen Research & Development, LLC, and were conducted collaboratively by the sponsor, an academic steering committee, and an academic research business, George Clinical. The sponsor was responsible for study oversight and data collection, and experienced a representative around the Steering Committee, which was responsible for study design, data analysis, data interpretation, and writing of this statement. All authors experienced full access to all the data and experienced final responsibility for the decision to submit for publication. Results The CANVAS Program randomized 10 142 participants with a imply follow-up TNFRSF10D period of 188.2 weeks. At baseline, 2039 (20.1%) participants had CKD (mean age, 68 years; blood pressure, 137/76 mm?Hg; HbA1c, 8.3%; eGFR, 49 mL/min/1.73 m2; median UACR, 22 mg/g), of whom 71.6% had a prior history of cardiovascular disease. This included 554 participants (5.5%) in the eGFR 45 mL/min/1.73 m2 category, among whom 73.3% had a history of cardiovascular disease. Baseline characteristics of participants with eGFR 45, 45 to 60, 60 to 90, and 90 mL/min/1.73 m2 are presented in Table ?Table1.1. In progressively lower categories of eGFR, participants were older and more likely to be female; be white; have a longer period of diabetes; have established micro- or macrovascular disease; have a history of.