Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

Alicia Smith, PharmD, First Light Health System

Background: Exploratory results of previous trials involving SGLT2 (sodium-glucose cotransporter 2) inhibitors, including the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME trials, have suggested that SGLT2 inhibitors may improve renal outcomes in patients with type 2 diabetes. These previous studies have shown improvement in renal outcomes in patients at low risk of developing kidney failure. Currently, data is limited surrounding renal outcomes of SGLT2 inhibitors when used in patients at high risk of developing renal failure.

Objective: To examine the effects of canagliflozin and placebo in decreasing the incidence of end stage kidney disease and death from renal or cardiovascular causes when used in patients with type 2 diabetes and albuminuric chronic kidney disease (CKD).

Study Design: This study is a randomized, double-blind, placebo controlled trial, which occurred across 690 sites in 34 countries. Exclusion criteria included the following: history of diabetic ketoacidosis or type 1 diabetes, non-diabetic renal disease, renal transplant or dialysis, uncontrolled hypertension, hyperkalemia at baseline, Class IV congestive heart failure, myocardial infarction/unstable angina/revascularization within 12 weeks of randomization, history of amputation, and pregnancy. Patients included in the trial were at least 30 years of age with type 2 diabetes and an A1C between 6.5-12%. Inclusion criteria included patients with CKD defined as an eGFR of 30-90 mL/min/1.73 m2 and albuminuria (urinary albumin:creatinine ratio >300 mg/g). Patients also needed to be treated with an angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) for at least four weeks prior to randomization. Patients were randomized to canagliflozin 100 mg by mouth daily or placebo. The primary outcome was a composite of end-stage kidney disease (dialysis, kidney transplant, eGFR <15 mL/min/1.73 m2), doubling of serum creatinine level from baseline, or death from renal or cardiovascular disease. 

Results: Out of a total of 4401 patients included in the study, the event rate per 1000 patient-years of the primary composite outcome in the canagliflozin group was 43.2, compared to 61.2 in the placebo group (HR 0.7 [95% CI 0.59 - 0.82], P=0.00001). In the end-stage renal disease component, the event rate per 1000 patient-years in the canagliflozin group was 20.4, compared to 29.4 in the placebo group (HR 0.68 [95% CI 0.54 - 0.86], P=0.002). In the doubling of serum creatinine component, the event rate per 1000 patient-years in the canagliflozin group was 20.7, compared to 33.8 in the placebo group (HR 0.6 [95% CI 0.48 - 0.76], P<0.001). For the components of renal and cardiovascular death, there were no significant between-group differences found. Subgroup analysis revealed that the patients with the greatest benefit in the primary composite outcome were those with an eGFR 45 to <60 mL/min/1.73 m2 (HR 0.52 [95% CI 0.38 - 0.72]) and those with a urinary albumin:creatinine ratio (UACR) >1000 mg/g (HR 0.67 [95% CI 0.55 - 0.81]). Diabetic ketoacidosis occurred more frequently in the canagliflozin group when compared to placebo, 2.2 versus 0.2 events per 1000 patient-years respectively (HR 10.8 [95% CI 1.39 - 83.65]). No significant differences were found between groups for the side effects of amputation, fracture, hyperkalemia, or acute kidney injury.

Conclusions: Canagliflozin was found to have a lower risk of the primary composite outcome (end-stage kidney disease [dialysis, kidney transplant, eGFR <15 mL/min/1.73 m2], doubling of serum creatinine level from baseline, or death from renal or cardiovascular disease) compared to placebo in patients with type 2 diabetes and CKD. Patients with the greatest potential benefit include those with an eGFR 45 - 60 mL/min/1.73 m2 and those with a UACR >1000 mg/g. A limitation of the study is that it was stopped at a planned interim analysis which may contribute to overestimating the effects found. Future research could explore if other SGLT2 inhibitors provide similar benefits as canagliflozin in patients with type 2 diabetes and CKD. 

Key Point: Canagliflozin may be an effective treatment option for patients with type 2 diabetes and CKD to provide renal and cardiovascular protection independent of blood glucose levels

Reference:

1. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306.