The New England Journal of Medicine June 13, 2019

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

Vlado Perkovic, Meg J. Jardine, Bruce Neal, et al.

Bottom Line

In patients with type 2 diabetes and albuminuric chronic kidney disease, canagliflozin significantly reduced the risk of kidney failure and cardiovascular events compared to placebo.

Key Findings

1. The relative risk of the primary composite outcome was reduced by 30% in the canagliflozin group (event rate 43.2 vs 61.2 per 1000 patient-years; HR 0.70; 95% CI 0.59-0.82; P=0.00001) [2.1].

2. The relative risk of the renal-specific composite (end-stage kidney disease, doubling of creatinine, or renal death) was reduced by 34% (HR 0.66; 95% CI 0.53-0.81; P<0.001).

3. Canagliflozin significantly lowered the risk of end-stage kidney disease by 32% (HR 0.68; 95% CI 0.54-0.86; P=0.002).

4. Cardiovascular benefits included a lower risk of cardiovascular death, myocardial infarction, or stroke (HR 0.80; 95% CI 0.67-0.95; P=0.01) and a substantial 39% reduction in hospitalization for heart failure (HR 0.61; 95% CI 0.47-0.80; P<0.001).

5. Importantly, there were no significant differences in the rates of lower-limb amputation or fracture between the canagliflozin and placebo groups, alleviating safety concerns raised by the previous CANVAS trial.

Study Design

Design

RCT

Double-Blind

Sample

4,401

Patients

Duration

2.62 yr

Median

Setting

Multicenter, global

Population Patients with type 2 diabetes and albuminuric chronic kidney disease (estimated GFR 30 to <90 ml/min/1.73m2 and urinary albumin-to-creatinine ratio 300 to 5000) receiving a stable dose of a renin-angiotensin system inhibitor.

Intervention Canagliflozin 100 mg once daily.

Comparator Matching placebo.

Outcome Composite of end-stage kidney disease (dialysis, transplantation, or sustained estimated GFR <15 ml/min/1.73m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes.

Study Limitations

• The trial was stopped early at a planned interim analysis due to overwhelming efficacy, which carries a risk of slightly overestimating the true treatment effect [2.1].

• The study excluded patients with non-albuminuric diabetic kidney disease or those with an eGFR below 30 ml/min/1.73m2 at screening, leaving uncertainty about the drug's efficacy in those specific populations at the time.

• The median follow-up of 2.62 years limited the ability to assess very long-term outcomes and safety.

Clinical Significance

CREDENCE marked a paradigm shift in the management of diabetic kidney disease, proving that canagliflozin safely and effectively delays the progression to end-stage kidney disease and reduces cardiovascular events when added to standard-of-care RAAS blockade. The definitive results led to rapid updates in major clinical guidelines, establishing SGLT2 inhibitors as a foundational, standard-of-care therapy for patients with type 2 diabetes and albuminuric chronic kidney disease.

Historical Context

For nearly two decades following the RENAAL and IDNT trials in 2001, ACE inhibitors and ARBs remained the only approved treatments to slow the progression of diabetic nephropathy. While cardiovascular outcome trials for SGLT2 inhibitors like EMPA-REG OUTCOME and CANVAS were primarily designed to ensure cardiovascular safety, they showed exploratory signals of profound renal protection. CREDENCE was designed as the first dedicated renal outcomes trial for an SGLT2 inhibitor in patients with established chronic kidney disease, seeking to confirm these secondary observations.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of canagliflozin specifically protect the kidneys in diabetic nephropathy independently of its glucose-lowering effects?

Key Response

Tests foundational understanding of SGLT2 inhibitors. SGLT2 inhibitors block glucose and sodium reabsorption in the proximal tubule. The increased distal sodium delivery to the macula densa restores tubuloglomerular feedback, leading to afferent arteriole vasoconstriction. This decreases intraglomerular pressure and reduces the hyperfiltration that is a key driver of diabetic nephropathy.

Resident

A patient with T2DM and an eGFR of 35 ml/min/1.73 m2 is starting canagliflozin based on the CREDENCE trial. What are the expected initial changes in renal function upon initiation, and how should this be managed?

Key Response

Focuses on clinical application and expected lab changes. Initiation of an SGLT2 inhibitor typically causes an acute, reversible dip in eGFR due to hemodynamic changes (reduced intraglomerular pressure). Residents must know not to panic or inappropriately stop the drug, as this acute dip is associated with long-term renal preservation and does not represent acute kidney injury.

Fellow

The CREDENCE trial was stopped early for efficacy during an interim analysis. How does stopping a trial early for benefit potentially impact the interpretation of the magnitude of both the primary renal outcomes and secondary cardiovascular endpoints?

Key Response

Explores advanced evidence interpretation. Stopping early for benefit can sometimes overestimate the treatment effect (the random high phenomenon). Fellows should critically evaluate whether the event rate was sufficient at the time of stoppage and how secondary endpoints might be underpowered or truncated, potentially affecting the robustness of those specific estimates.

Attending

Given the robust cardiorenal benefits demonstrated in CREDENCE, how do you navigate the real-world barriers of polypharmacy and the risk of lower-extremity amputations (noted in the earlier CANVAS trial) when prescribing canagliflozin to an older, frail patient with advanced diabetic kidney disease?

Key Response

Emphasizes practice-changing implications and nuanced risk-benefit discussions. Attendings must weigh the robust NNT for preventing renal failure against potential harms like amputations (seen in CANVAS, though not significantly elevated in CREDENCE), cost issues, and patient-specific factors such as prior foot ulcers or severe peripheral artery disease.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

CREDENCE utilized a hierarchical testing sequence for its secondary endpoints to control for type I error. How does this specific statistical approach limit or enhance the inferential claims we can make regarding the secondary cardiovascular outcomes, particularly given the early termination of the trial?

Key Response

Focuses on statistical methodology. A hierarchical testing sequence means if a primary or preceding secondary endpoint fails to reach significance, subsequent tests are considered exploratory. Because the trial was stopped early, the power for events lower in the hierarchy might be compromised, complicating the formal hypothesis testing for specific cardiovascular outcomes.

Journal Editor

As a reviewer, what concerns would you raise regarding the generalizability of the CREDENCE findings to patients with non-albuminuric diabetic kidney disease or those with advanced CKD (eGFR under 30) who were excluded from enrollment?

Key Response

Evaluates critical appraisal and external validity. The study specifically enrolled patients with macroalbuminuria (UACR over 300) and eGFR over 30. A tough reviewer would flag that the results cannot be strictly extrapolated to the growing phenotype of non-proteinuric diabetic kidney disease or stage 4/5 CKD, highlighting the need for subsequent broader trials.

Guideline Committee

How does the CREDENCE trial mandate a shift in the KDIGO and ADA guidelines regarding first-line therapy for T2DM and CKD, and what specific eGFR and UACR thresholds should be recommended for SGLT2 inhibitor initiation based on this evidence?

Key Response

Addresses guidelines directly. CREDENCE provided Grade 1A evidence that shifted KDIGO and ADA guidelines to recommend SGLT2 inhibitors alongside metformin as first-line therapy for patients with T2DM, eGFR over 30, and UACR over 300 mg/g. The committee must codify these initiation thresholds while noting that the drug can be continued even if eGFR drops below 30 until dialysis is initiated.

Clinical Landscape

Noteworthy Related Trials

2015

EMPA-REG OUTCOME

n = 7,020 · NEJM

Tested

Empagliflozin 10mg or 25mg daily

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Empagliflozin significantly reduced cardiovascular mortality and showed secondary outcomes of reduced incident or worsening nephropathy.

2017

CANVAS Program

n = 10,142 · NEJM

Tested

Canagliflozin 100mg or 300mg daily

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Canagliflozin reduced cardiovascular events and indicated potential renal protection, alongside an increased risk of lower-extremity amputations.

2020

DAPA-CKD

n = 4,304 · NEJM

Tested

Dapagliflozin 10mg daily

Population

Patients with chronic kidney disease, with or without T2DM

Comparator

Placebo

Endpoint

Composite of sustained >=50% decline in eGFR, ESKD, or renal/CV death

Key result: Dapagliflozin significantly reduced the risk of the primary composite endpoint and all-cause mortality compared to placebo.

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