Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy
By Aly Becraft, MS and Kevin C Maki, PhD
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was designed to assess the effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor, canagliflozin, on renal outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease.1,2 This randomized, double-blind, placebo-controlled, multicenter clinical trial included patients of at least 30 years of age with an estimated glomerular filtration rate of 30 to <90 mL per minute per 1.73 m2 of body-surface area, albuminuria, and a glycated hemoglobin level of 6.5 to 12.0%. Patients were randomized to receive a 100 mg daily dose of canagliflozin or placebo added to renin-angiotensin-aldosterone blockade. The primary outcome was a composite of end stage renal disease (ESRD), doubling of the serum creatinine level for at least 30 days, or death from renal or cardiovascular (CV) disease. Secondary outcomes were tested hierarchically in the following order:
- composite of CV death or hospitalization for heart failure (HF)
- composite of CV death, myocardial infarction (MI) or stroke
- hospitalization for HF
- composite of ESRD, doubling of the serum creatinine level or renal death
- CV death
- death from any cause
- composite of CV death, MI, stroke, or hospitalization for HF or for unstable angina (UA)
The trial design was event driven; after a planned interim analysis, the trial was stopped early due to the requisite number of primary outcome events having been achieved. The final analysis included 4401 randomized patients and a median follow up time of 2.62 years. The results for the outcomes, including the hazard ratios (HR) and 95% confidence intervals (CI), are shown in the table below.
|
Outcome |
Canagliflozin (n = 2202) |
Placebo (n = 2199) |
HR (95% CI) |
p-value |
|
|
Events/1000 patient-years |
|||||
|
Primary composite outcome |
43.2 |
61.2 |
0.70 (0.59, 0.82) |
0.00001 |
|
|
Secondary outcomes |
|||||
|
CV death or hospitalization for HF |
31.5 |
45.4 |
0.69 (0.57, 0.83) |
<0.001 |
|
|
CV death, MI or stroke |
38.7 |
48.7 |
0.80 (0.67, 0.95) |
0.01 |
|
|
Hospitalization for HF |
15.7 |
25.3 |
0.61 (0.47, 0.80) |
<0.001 |
|
|
ESRD, doubling of serum creatinine level or renal death |
27.0 |
40.4 |
0.66 (0.53, 0.81) |
<0.001 |
|
|
CV death |
19.0 |
24.4 |
0.78 (0.61, 1.00) |
0.05* |
|
*No significant between-group difference in the risk of CV death was observed, so the differences in all subsequent outcomes in the hierarchical testing sequence were not formally tested.
Conclusion: Compared to placebo, canagliflozin lowered risk of kidney failure and CV events after a median follow-up of 2.62 years, supporting efficacy as a treatment option for renal and CV protection in patients with T2D and chronic kidney disease.
References:
- Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019; Epub ahead of print.
- Ingelfinger JR, Rosen CJ. Clinical credence – SGLT2 inhibitors, diabetes, and chronic kidney disease. N Engl J Med. 2019; Epub ahead of print.
