PracticeUpdate Conference Series ISN WCN 2019

canagliflozin therapy was 0.72 (95% CI 0.54–0.97). These effects were consistent regardless of baseline eGFR or UACR, as well as other baseline characteristics. While eGFR dropped more in the treat- ment than the placebo group during the first weeks after randomization, this rapidly attenuated. By 42 months, eGFR had dropped by a mean of –1.85 mg/mL/ min/1.73 m 2 per year in the canagliflozin group and a mean of –4.59 mg/mL/ min/1.73 m 2 per year in the placebo group, which translated to a 60% reduction in eGFR slope decline. Cardiovascular and safety outcomes were similarly promising. Comparing active therapy with placebo yielded superior outcomes with respect to the compositive of cardiovascular death or hospitaliza- tion from heart failure (HR 0.69; 95% CI 0.57–0.83; P < .001), cardiovascular death, myocardial infarction or stroke (HR 0.80; 95% CI 0.67–0.95; P = .01), hospitalization for heart failure (HR 0.61; 95% CI 0.47– 0.80; P < .001), and cardiovascular death (HR 0.78; 95% CI 0.61–1.00; P = .0502). No differences were found between the two groups of patients with respect to risk of fracture or amputation. The safety profile of canagliflozin was consistent with other studies of this drug. In his presentation on the clinical impli- cations of CREDENCE, David C. Wheeler, MD, of University College London in the United Kingdom, pointed out that, among patients with an eGFR of 30 to 45 mL/ min/1.73 m 2 , only 16 patients would need to be treated for 2.5 years to prevent a clinical outcome. “Canagliflozin safely reduced the risk of kidney failure and pre- vented cardiovascular events in people with type 2 diabetes and chronic kidney disease,” he concluded. bigger numbers, so this is a huge epidemic with major consequences. " the leading cause of people requiring renal replacement therapy, and this problem is also headed for much " Diabetes is by far

glomerular filtration rate (eGFR) of 30 to 90 mL/min/1.73 m 2 as well as a urinary albumin-to-creatinine ratio (UACR) of 3000 to 5000 mg/g were randomized to canagliflozin 100 mg once daily or placebo. Patients were followed up at week 3, 13 and 26, then every 13 weeks thereafter. Prior to randomization, all patients were receiving standard of care therapy, includ- ing a maximum tolerated dose of an ACE inhibitor or angiotensin II receptor blocker. Patients were maintained on treatment regardless of eGFR decline or devel- opment of an eGFR <30 mL/min/1.73 m 2 , unless they received chronic dialysis or received a kidney transplant. The patients’ mean age was 63 years, and 34% were female. The mean duration of diabetes was 16 years. Overall, 97% of par- ticipants had hypertension, 15% had heart failure (New York Heart Association class I to III), 50% had cardiovascular disease, and 5% had received a prior amputation. These and other characteristics, including

background therapy and renal character- istics, were well-balanced between the treatment and placebo groups. In July 2018, after a planned interim anal- ysis, the CREDENCE trial was stopped prematurely for efficacy reasons. The primary endpoint was the compos- ite of ESKD (defined as chronic dialysis for ≥30 days, kidney transplantation or eGFR <15 mg/mL/min/1.73m 2 for ≥30 days), doubling of serum creatinine, or renal or cardiovascular death. This occurred in 245 patients on active therapy and 340 patients on placebo (hazard ratio 0.70; 95% confidence interval 0.59–0.82; P = .00001). Looking at the renal composite endpoint of ESKD, doubling of serum creatinine, or renal death yielded a hazard ratio of 0.66 (95% CI 0.53–0.81; P < .001) with canagliflozin, compared with placebo. The hazard ratio for ESKD alone was 0.68 (95% CI 0.54–0.86; P = .002). For the composite of dialysis, kidney transplanta- tion or renal death, the hazard ratio with

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WCN 2019 • PRACTICEUPDATE CONFERENCE SERIES