The substantial increase in the prevalence of end-stage renal disease worldwide is accounted for, in part, by the increasing prevalence of type 2 diabetes. It is estimated that more than 3 million people are being treated for kidney failure worldwide, a number that is expected to increase to more than 5 million by 2035. Currently renin-angiotensin system blockade is the only approved treatment for renoprotection in patients with type 2 diabetes.
In previous trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), agents developed to lower blood glucose levels in patients with type 2 diabetes, researchers found reductions in cardiovascular events with SGLT2 inhibitors. Secondary analyses suggested that there might be improvement in renal outcomes with SGLT2 inhibition.
The CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial was designed to examine the effects of the SGLT2 inhibitor canagliflozin on renal outcomes in patients with type 2 diabetes and albuminuric chronic kidney disease (CKD). Vlado Perkovic, MBBS, PhD, and colleagues reported results of the CREDENCE trial online in the New England Journal of Medicine [doi:10.1056/NEJMoa1811744].
In this double-blind, randomized trial, patients with type 2 diabetes and albuminuric CKD were assigned to either canagliflozin 100 mg daily or placebo. All patients had estimated glomerular filtration rate (eGFR) of 30 to <90 mL/min/1.73 m2 and albuminuria, defined as ratio of albumin (mg) to creatinine (g]), >300 to 5000. The primary outcome of interest was a composite of end-stage renal disease (ESRD), defined as dialysis, transplantation, or sustained eGFR of <15 mL/min/1.73 m2; a doubling of serum creatinine level; or death from renal or cardiovascular causes.
Secondary outcomes were prespecified for sequential hierarchical testing: (1) composite of cardiovascular death or hospitalization for heart failure; (2) composite of cardiovascular death, myocardial infarction (MI), or stroke; (3) hospitalization for heart failure; (4) composite of ESRD, doubling of the serum creatinine level, or renal death; (5) cardiovascular death; (6) death from any cause; and (7) composite of cardiovascular death, MI, or hospitalization for heart failure or for unstable angina. All other efficacy outcomes were exploratory.
A total of 12,900 patients were screened from March 2014 through May 2017. Of those, 4401 underwent randomization at 690 sites in 34 countries. The two groups were similar in baseline characteristics: mean age was 63 years, 33.9% were women, mean glycated hemoglobin value was 8.3%, mean eGFR was 56.2 mL/min/1.73 m2, and the median urinary albumin-to-creatine ratio was 927.
By July 2018, the requisite number of primary outcome events to trigger the interim analysis were accrued. The data monitoring committee advised the CREDENCE steering committee members that the prespecified efficacy criteria for early cessation had been reached and recommended that the trial be stopped. Patients were recalled for final visits and the trial was concluded. At trial conclusion at a median follow-up of 2.62 years, 27.3% (n=1201) of patients in the two groups had discontinued therapy. During follow-up, trial adherence rate was 84%.
In the canagliflozin group, the event rate of the primary composite outcome of ESRD, doubling of serum creatinine level, or renal or cardiovascular death was significantly lower than in the placebo group: 43.2 per 1000 patient-years versus 61.2 per 1000 patient-years, respectively. The relative risk in the canagliflozin group was 30% lower than in the placebo group: hazard ratio (HR), 0.70; 95% confidence interval (CI), 0.59-0.82; P=.00001). Across regions and other prespecified groups, the effects were consistent, as they were for the components of ESRD (HR, 0.68; 95% CI, 0.54-0.86; P=.002).
The effects were also consistent across renal components: doubling of serum creatinine level, HR, 0.60; 95% CI, 0.48-0.76; P<.001 and the exploratory outcome of dialysis, kidney transplantation, or renal death, HR, 0.72; 95% CI, 0.54-0.97. Results were nearly identical in sensitivity analyses that included imputation of missing data (HR, 0.69; 95% CI, 0.59-0.82) or after adjustment for competing risks (HR, 0.70; 95% CI, 0.59-0.82).
When the secondary outcomes were tested in a hierarchical fashion, patients in the canagliflozin group also had a lower risk of several of prespecified outcomes, including composites of cardiovascular death or hospitalization for heart failure (HR, 0.69; 95% CI, 0.57-0.83; P<.001), cardiovascular death, MI, or stroke (HR, 0.80; 95% CI, 0.67-0.95; P=.01), and hospitalization for heart failure (HR, 0.61; 95% CI, 0.47-0.80; P<.001). In the canagliflozin group, the relative risk of the composite of ESRD, doubling of serum creatinine, or renal death was lower by 34% (HR, 0.66; 95% CI, 0.53-0.81; P<.001).
There were no significant differences between the two groups in the risk of cardiovascular death. The differences in all subsequent outcomes in the hierarchical testing sequence were not formally tested.
The rates of adverse events and serious adverse events were similar overall in the two groups. There were no significant differences in the risk of lower limb amputation: 12.3 per 1000 patient-years in the canagliflozin group versus 11.2 per 1000 patient-years in the placebo group (HR, 1.11; 95% CI, 0.79-1.56). The rates of fracture were also similar in the two groups (HR, 0.98; 95% CI, 0.70-1.37). The rates of diabetic ketoacidosis were low overall, but higher in the canagliflozin group compared with the placebo group (2.2 per 1000 patient-years vs 0.2 per 1000 patient-years).
The researchers cited some limitations to the study, including stopping the trial early at a planned interim analysis, not measuring off-treatment eGFR levels in patients who had completed the trial, and excluding patients with very advanced kidney disease (eGFR <30 mL/min/1.73 m2).
The researchers said, “In conclusion, among patients with type 2 diabetes and kidney disease, those in the canagliflozin group had a lower risk of kidney failure and cardiovascular events than those in the placebo group at a median follow-up of 2.62 years.”
- The CREDENCE trial was designed to examine the effects of the sodium-glucose cotransporter 2 inhibitor canagliflozin on renal outcomes in patients with type 2 diabetes and albuminuric chronic kidney disease.
- The primary outcome of interest was a composite of end-stage renal disease, a doubling of serum creatinine level, or death from renal or cardiovascular causes.
- At a median follow-up of 2.62 years, the relative risk among patients in the canagliflozin group for the primary outcome was 30% lower than in the placebo group. There were no significant differences in the rates of amputation or fracture between the two groups.