Cardiovascular and Renal Outcomes With Canagliflozin According to Baseline Kidney Function

Abstract

Background: Canagliflozin is approved for glucose lowering in type 2 diabetes and confers cardiovascular and renal benefits. We sought to assess whether it had benefits in people with chronic kidney disease, including those with an estimated glomerular filtration rate (eGFR) between 30 and 45 mL/min/1.73 m2 in whom the drug is not currently approved for use.

Methods: The CANVAS Program randomized 10 142 participants with type 2 diabetes and eGFR >30 mL/min/1.73 m2 to canagliflozin or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with other cardiovascular, renal, and safety outcomes. This secondary analysis describes outcomes in participants with and without chronic kidney disease, defined as eGFR <60 and ≥60 mL/min/1.73 m2, and according to baseline kidney function (eGFR <45, 45 to <60, 60 to <90, and ≥90 mL/min/1.73 m2).

Results: At baseline, 2039 (20.1%) participants had an eGFR <60 mL/min/1.73 m2, 71.6% of whom had a history of cardiovascular disease. The effect of canagliflozin on the primary outcome was similar in people with chronic kidney disease (hazard ratio, 0.70; 95% CI, 0.55-0.90) and those with preserved kidney function (hazard ratio, 0.92; 95% CI, 0.79-1.07; P heterogeneity = 0.08). Relative effects on most cardiovascular and renal outcomes were similar across eGFR subgroups, with possible heterogeneity suggested only for the outcome of fatal/nonfatal stroke ( P heterogeneity = 0.01), as were results for almost all safety outcomes.

Conclusions: The effects of canagliflozin on cardiovascular and renal outcomes were not modified 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: NCT01032629, NCT01989754.

Keywords: canagliflozin; cardiovascular diseases; diabetes mellitus, type 2; glomerular filtration rate; kidney; renal insufficiency, chronic; sodium glucose cotransporter 2; treatment outcome.

Figures

Figure 1.

Changes in intermediate outcomes with canagliflozin compared to placebo in participants with eGFR <45, 45 to <60, 60 to <90, and ≥90 mL/min/1.73 m2 at baseline. Represents the mean difference in change from baseline between canagliflozin and placebo from post-baseline to end of follow-up, except for UACR, where it is percent change in the geometric mean of canagliflozin relative to placebo. BP indicates blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, glycohemoglobin; and UACR, urinary albumin/creatinine ratio.

Figure 2.

Effects of canagliflozin on cardiovascular and renal outcomes in participants according to baseline eGFR categories <45, 45 to <60, 60 to <90, and ≥90 mL/min/1.73 m2. CV indicates cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; HR, hazard ratio; MACE, major adverse cardiovascular event; and MI, myocardial infarction. *Renal composite: 40% decrease in eGFR, end-stage kidney disease, or renal death.

Figure 3.

Effect on eGFR slope from week 6/13 until end of follow-up in participants with eGFR <45, 45 to <60, 60 to <90, and ≥90 mL/min/1.73 m2 at baseline. eGFR indicates estimated glomerular filtration rate; and SE, standard error. *Data are mean±SE. †Data are reported for week 6 in CANVAS and week 13 in CANVAS-R.

Figure 4.

Adverse events across the CANVAS Program in participants with eGFR <45, 45 to <60, 60 to <90, and ≥90 mL/min/1.73 m2 at baseline. eGFR indicates estimated glomerular filtration rate; and HR, hazard ratio.

Figure 6.

Absolute benefits and risks per 1000 patients over 5 years with canagliflozin versus placebo in the overall population and in participants with eGFR <45, 45 to <60, 60 to <90, and ≥90 mL/min/1.73 m2 at baseline. eGFR indicates estimated glomerular filtration rate; HF, heart failure; and MACE, major adverse cardiovascular event. *Excess number is relative to the placebo group. If the number is negative, then fewer participants in the canagliflozin group experienced the event compared to the placebo group. †Renal composite: 40% decrease in eGFR, end-stage kidney disease, or renal death.

Figure 5.

Adverse events collected in CANVAS alone in participants with eGFR ≤45, 45 to <60, 60 to <90, and ≥90 mL/min/1.73 m2 at baseline. The annualized incidence rates, estimates for HRs, and 95% CIs are reported for the CANVAS study alone through January 7, 2014, because after this time, only serious adverse events or adverse events leading to study drug discontinuation, or selected adverse events of interest were collected. eGFR indicates estimated glomerular filtration rate; and HR, hazard ratio. *Note that 1 patient in the placebo group who experienced an event had a missing baseline eGFR value; therefore, this patient is only counted in the overall total. †Data collected in CANVAS and CANVAS-R. Includes infections of male genitalia and phimosis and excludes circumcision.