CREDENCE – Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy
Carol Pollock, MBBS, PhD, FRACP, AAHMS
Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Australia Hiddo Lambers Heerspink, PharmD, PhD
George Institute for Global Health, University of New South Wales, Sydney, Australia Kenneth W. Mahaffey, MD
Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, USA
In several trials designed to meet regulatory requirements for cardiovascular safety of sodium-glucose cotransporter 2 (SGLT2) inhibitors, reductions in cardiovascular events were seen. Secondary and exploratory analyses of these trials suggested that SGLT2 inhibition might improve renal outcomes.
All patients had an estimated glomerular filtration rate (eGFR) of 30 to <90 mL/min/1.73 m2 and albuminuria (ratio of albumin (mg) to creatinine (g), >300 to 5000) and were treated with renin–angiotensin system blockade.
Total patients randomised: 4401.
Canagliflozin 100 mg/day (n = 2202).
Placebo (n = 2199).
Primary outcome measure
Composite of end-stage kidney disease (ESKD – dialysis, transplantation, or a sustained eGFR of <15 mL/min/1.73 m2), a doubling of serum creatinine level, or death from renal or cardiovascular causes.
The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee, after having randomised 4401 patients with a median follow-up of 2.62 years.
The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (HR, 0.70; 95% CI, 0.59-0.82; P = 0.00001).
The relative risk of the renal-specific composite of ESKD, a doubling of the creatinine level, or death from renal causes was lower by 34% (HR, 0.66; 95% CI, 0.53-0.81; P <0.001), and the relative risk of ESKD was lower by 32% (HR, 0.68; 95% CI, 0.54-0.86; P = 0.002).
The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (HR, 0.80; 95% CI, 0.67-0.95; P = 0.01) and hospitalisation for heart failure (HR, 0.61; 95% CI, 0.47-0.80; P <0.001).
Canagliflozin reduced the risk of major cardiovascular events overall (HR, 0.80 (95% CI, 0.67-0.95); P=0.01), with consistent reductions in both the primary (HR, 0.68 (95% CI, 0.49-0.94)) and secondary (HR, 0.85 (95% CI, 0.69-1.06)) prevention groups (P for interaction = 0.25).
The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalisation for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome).
In patients with type 2 diabetes and CKD, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years.
The reduced risk was also seen in participants who did not have previous cardiovascular disease.
Key Messages/Clinical Perspectives
Based on the results of CREDENCE, the American Diabetes Association recently updated the Standards of Care with renal guidance, stating that “For patients with type 2 diabetes and diabetic kidney disease, consider use of an SGLT2 inhibitor in patients with an eGFR ≥30 mL/min/1.73m2 and particularly in those with >300 mg/g albuminuria to reduce risk of CKD progression, cardiovascular events, or both.”
Mahaffey KW, Jardine MJ, Bompoint S, et al. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. Circulation 2019 Aug 27;140(9):739-50