Series: Landmark Trials in Endocrinology & Metabolism | Study #4
Category: SGLT2 Inhibitors · Renal Protection | Design: Multicentre, double-blind, placebo-controlled RCT | n: 4,401 | Follow-up: 2.62 years (median; stopped early)
📋 Summary
Authors: Perkovic V et al., for the CREDENCE Trial Investigators
Journal: N Engl J Med 2019;380:2295–2306 | DOI: 10.1056/NEJMoa1811744
CREDENCE was designed specifically to test whether canagliflozin could reduce the progression of chronic kidney disease in patients with type 2 diabetes mellitus, a question the preceding cardiovascular outcomes trials had not been powered to answer definitively. A total of 4,401 patients with type 2 diabetes, an estimated glomerular filtration rate (eGFR) of 30 to less than 90 ml/min/1.73 m², and significant albuminuria (urine albumin-to-creatinine ratio greater than 300 to 5,000 mg/g) who were already receiving maximum tolerated doses of renin-angiotensin system blockade were randomly assigned to canagliflozin 100 mg once daily or placebo. The primary composite outcome comprised end-stage kidney disease (defined as dialysis, renal transplantation, or a sustained eGFR below 15 ml/min/1.73 m²), a doubling of serum creatinine sustained over at least 30 days, or death from renal or cardiovascular causes. The trial was stopped early on the recommendation of the independent data and safety monitoring committee following a planned interim analysis demonstrating clear efficacy. At the time of stopping, the relative risk of the primary outcome was 30% lower in the canagliflozin group (event rates 43.2 vs 61.2 per 1,000 patient-years; HR 0.70; 95% CI 0.59 to 0.82; p=0.00001). The renal-specific composite of end-stage kidney disease, creatinine doubling, or death from renal causes was reduced by 34% (HR 0.66; 95% CI 0.53 to 0.81; p<0.001), and end-stage kidney disease alone by 32% (HR 0.68; 95% CI 0.54 to 0.86; p=0.002). Canagliflozin also reduced the risk of 3-point MACE (HR 0.80; 95% CI 0.67 to 0.95; p=0.01) and hospitalisation for heart failure (HR 0.61; 95% CI 0.47 to 0.80; p<0.001). Importantly, no significant difference was observed in amputation risk between groups, which had been a concern following the CANVAS Programme findings.
📊 Key Findings
| Outcome | Canagliflozin | Placebo | Effect Size |
|---|---|---|---|
| Primary composite (ESKD, creatinine doubling, renal/CV death) | 43.2/1,000 PY | 61.2/1,000 PY | HR 0.70 (0.59–0.82) · p=0.00001 · 30% RRR |
| Renal-specific composite (ESKD, creatinine doubling, renal death) | — | — | HR 0.66 (0.53–0.81) · p<0.001 · 34% RRR |
| End-stage kidney disease alone | — | — | HR 0.68 (0.54–0.86) · p=0.002 · 32% RRR |
| 3-point MACE (CV death, MI, stroke) | — | — | HR 0.80 (0.67–0.95) · p=0.01 |
| HF hospitalisation | — | — | HR 0.61 (0.47–0.80) · p<0.001 · 39% RRR |
| Amputation | — | — | No significant difference |
| Absolute risk reduction (primary composite) | ~18/1,000 PY difference | NNT approximately 20 over 2.62 years | |
💬 Expert Commentary
CREDENCE represented a genuinely pivotal moment in the management of diabetic nephropathy. Prior to its publication, the only agents with established renal protection in this setting were those targeting the renin-angiotensin system, notably the angiotensin receptor blockers losartan and irbesartan, whose benefit on hard renal endpoints had been demonstrated some 15 to 17 years earlier in the RENAAL and IDNT trials. CREDENCE was the first trial in nearly two decades to demonstrate a substantial reduction in the risk of kidney failure with a new therapeutic class, and it did so on a background of established RAS blockade, confirming an additive mechanism rather than a shared one. The haemodynamic basis for the renal benefit of SGLT2 inhibition, primarily via tubuloglomerular feedback restoration reducing intraglomerular hypertension, is mechanistically distinct from the vasodilatory effect of angiotensin pathway inhibition, and CREDENCE provided the first hard endpoint evidence that these effects translate into a clinically meaningful reduction in the progression to dialysis or transplantation. The magnitude of effect, a 30% reduction in the primary composite with a NNT of approximately 20 over 2.62 years in a population with established nephropathy, is among the largest renal protective effects ever demonstrated in a prospective RCT in this indication.
The resolution of the amputation signal seen in CANVAS is notable and warrants comment. The nearly doubled amputation risk observed with canagliflozin in CANVAS had generated considerable clinical concern. In CREDENCE, no significant increase in amputation risk was detected, and the rates were numerically similar between groups. This discordance likely reflects differences in patient selection, the lower canagliflozin dose used (100 mg throughout rather than the 300 mg used in a substantial proportion of CANVAS participants), and possibly the targeted enrolment of a population already receiving intensive vascular risk management. The cardiovascular benefits observed in CREDENCE, including a 20% reduction in MACE and a 39% reduction in heart failure hospitalisation, were secondary findings in a renally enriched population and further reinforced the complementary cardiorenal profile of the SGLT2 inhibitor class. The early stopping of the trial, while justified on ethical grounds by the strength of the efficacy signal, introduces some uncertainty in the precision of effect size estimates.
Limitations: The trial was stopped early, which may have resulted in an overestimate of the treatment effect magnitude. Patients with an eGFR below 30 ml/min/1.73 m² were excluded, limiting generalisability to the most severely impaired patients. The relatively short median follow-up of 2.62 years does not allow assessment of very long-term renal outcomes. The study was industry-sponsored by Janssen Research and Development.
🔑 BOTTOM LINE
CREDENCE established canagliflozin as the first SGLT2 inhibitor to demonstrate a substantial reduction in hard renal endpoints in patients with type 2 diabetes and established albuminuric nephropathy on background RAS blockade, reducing the risk of kidney failure by approximately 30% and making SGLT2 inhibition a cornerstone of nephroprotective therapy alongside angiotensin system blockade.
⭐ Clinical Impact Rating: ●●●●● Practice-defining
Next in the series: Study #5 DAPA-HF: Dapagliflozin in Heart Failure with Reduced Ejection Fraction
