The New England Journal of Medicine AUGUST 17, 2017

Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

Bruce Neal, Vlado Perkovic, Kenneth W. Mahaffey, et al., on behalf of the CANVAS Program Collaborative Group

Bottom Line

The CANVAS Program demonstrated that canagliflozin reduced the risk of major adverse cardiovascular events and hospitalization for heart failure in patients with type 2 diabetes at high cardiovascular risk, though it was associated with an increased risk of lower-limb amputation.

Key Findings

1. The primary composite outcome (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) occurred in 26.9 participants per 1,000 patient-years in the canagliflozin group compared to 31.5 per 1,000 patient-years in the placebo group (hazard ratio, 0.86; 95% CI, 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority).

2. Canagliflozin treatment was associated with a 33% reduction in the risk of hospitalization for heart failure (hazard ratio, 0.67; 95% CI, 0.52 to 0.87).

3. There was a significant increase in the risk of lower-limb amputation with canagliflozin (6.3 vs. 3.4 participants per 1,000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75).

4. Progression of albuminuria was reduced in the canagliflozin group (89.4 vs. 128.7 participants per 1,000 patient-years; hazard ratio, 0.73; 95% CI, 0.67 to 0.79).

Study Design

Design

RCT

Double-Blind

Sample

10,142

Patients

Duration

2.4 yr

Median

Setting

Multicenter, International

Population Participants with type 2 diabetes and high cardiovascular risk (established disease or age ≥50 with ≥2 risk factors).

Intervention Canagliflozin (100 mg or 300 mg daily).

Comparator Matching placebo.

Outcome Composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

Study Limitations

• The program utilized integrated data from two trials (CANVAS and CANVAS-R) which had different follow-up durations.

• The observed increase in amputation risk was an unexpected finding that warrants caution and further investigation.

• Data collection for some adverse events was modified during the trial, potentially affecting the granularity of safety reporting.

• The study population was primarily restricted to patients with type 2 diabetes and high cardiovascular risk, which may limit the generalizability to lower-risk populations.

Clinical Significance

The results established canagliflozin as an effective therapeutic option for reducing major adverse cardiovascular events and heart failure hospitalizations in patients with type 2 diabetes at high cardiovascular risk, shifting the focus of diabetes management toward cardiovascular protection.

Historical Context

Following the EMPA-REG OUTCOME trial, which first demonstrated cardiovascular benefits of empagliflozin, the CANVAS Program served as a critical validation for the cardiovascular protective class effect of SGLT2 inhibitors in a broad population of patients with type 2 diabetes.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Based on the mechanism of SGLT2 inhibition in the proximal convoluted tubule, why does canagliflozin provide cardiovascular benefits even in patients whose blood glucose levels are only minimally affected?

Key Response

SGLT2 inhibitors like canagliflozin work by blocking the reabsorption of glucose and sodium in the kidney. This leads to natriuresis and osmotic diuresis, which reduces plasma volume, lowers blood pressure, and decreases cardiac preload and afterload. These hemodynamic changes provide cardiovascular protection, particularly in heart failure, independent of the drug's glycemic (HbA1c lowering) effects.

Resident

The CANVAS trial identified a significant increase in lower-limb amputations. Which patient comorbidities would make you most hesitant to prescribe canagliflozin, and what clinical monitoring should be implemented?

Key Response

The trial showed a nearly two-fold increase in the risk of amputation, primarily at the level of the toe or metatarsal. Residents should be cautious in patients with a history of prior amputation, peripheral vascular disease (PVD), or severe peripheral neuropathy. Management includes baseline and periodic foot examinations, as well as counseling patients on meticulous foot hygiene and the need to report any new ulcers or infections immediately.

Fellow

How does the 'tubuloglomerular feedback' mechanism explain both the initial acute dip in eGFR and the long-term renal preservation observed in the CANVAS renal outcomes?

Key Response

SGLT2 inhibitors increase sodium delivery to the macula densa. This triggers tubuloglomerular feedback, leading to afferent arteriolar vasoconstriction. This reduces intraglomerular hypertension, causing an initial, reversible 'dip' in eGFR (hemodynamic effect). However, by reducing glomerular hyperfiltration and barotrauma to the nephron, it prevents long-term structural damage and slows the progression of chronic kidney disease compared to the steady decline seen in the placebo group.

Attending

In light of the CANVAS results, how should we re-evaluate the traditional 'treat-to-target' HbA1c paradigm for a type 2 diabetic patient with established atherosclerotic cardiovascular disease (ASCVD)?

Key Response

CANVAS demonstrates that the selection of an agent with proven cardiorenal benefit is more important for mortality and morbidity than the absolute reduction in HbA1c alone. This suggests a practice shift where SGLT2 inhibitors (and GLP-1 RAs) should be prioritized for organ protection in high-risk patients regardless of whether their baseline A1c is already at target, moving from a glucose-centric model to a risk-reduction model.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The CANVAS Program integrated data from two separate trials (CANVAS and CANVAS-R) into a single analysis. What are the methodological advantages and potential pitfalls of this 'Integrated Analysis' approach regarding the detection of rare safety signals like the amputation risk?

Key Response

Pooling the trials (integrated analysis) increased the statistical power to detect major adverse cardiovascular events (MACE) and rare adverse events that individual trials might be underpowered to see. However, potential pitfalls include heterogeneity in trial design (CANVAS-R was focused on renal outcomes) and recruitment periods. For the amputation signal, the consistency across both trials strengthened the finding, but PhDs must ensure that different outcome definitions or monitoring frequencies between the two cohorts didn't introduce detection bias.

Journal Editor

If the amputation risk had been identified early in the CANVAS-R recruitment phase, would the editorial priority have shifted to require a pre-planned meta-analysis with other SGLT2i trials before publication, and why?

Key Response

A seasoned editor would flag the amputation signal as a potential 'class effect' versus a 'drug-specific' safety issue. If identified early, there would be pressure to determine if this was a random finding or a systemic risk. Rigorous peer review would demand a detailed subgroup analysis to see if the hazard was driven by specific baseline characteristics (like diuretic use or baseline PVD) to ensure the journal does not disseminate a signal that might cause unnecessary alarm without context.

Guideline Committee

How do the findings of the CANVAS Program regarding the reduction in MACE and HF compare to the EMPA-REG OUTCOME results, and should guidelines differentiate between SGLT2 inhibitors for specific cardiovascular indications?

Key Response

Both CANVAS and EMPA-REG showed reductions in MACE and heart failure hospitalization, supporting a class effect for cardiovascular protection. Current ADA and ACC/AHA guidelines generally recommend SGLT2 inhibitors with proven benefit for patients with ASCVD or heart failure. While the amputation signal led to an initial FDA boxed warning for canagliflozin (later removed), the guidelines emphasize caution in high-risk feet rather than a preference for one agent over the other, as the primary cardiorenal benefits appear consistent across the class.

Clinical Landscape

Noteworthy Related Trials

2015

EMPA-REG OUTCOME Trial

n = 7,020 · NEJM

Tested

Empagliflozin 10/25mg daily

Population

T2DM patients with established CVD

Comparator

Placebo

Endpoint

3-point MACE

Key result: Empagliflozin significantly reduced the risk of 3-point MACE, CV death, and hospitalization for heart failure.

2019

DECLARE-TIMI 58 Trial

n = 17,160 · NEJM

Tested

Dapagliflozin 10mg daily

Population

T2DM patients with established CVD or multiple risk factors

Comparator

Placebo

Endpoint

MACE and CV death/hospitalization for heart failure

Key result: Dapagliflozin met the primary endpoint of reducing heart failure hospitalizations and showed a favorable safety profile.

2019

CREDENCE Trial

n = 4,401 · NEJM

Tested

Canagliflozin 100mg daily

Population

T2DM patients with chronic kidney disease and albuminuria

Comparator

Placebo

Endpoint

Composite of end-stage kidney disease, doubling of serum creatinine, or renal/CV death

Key result: Canagliflozin significantly reduced the risk of kidney failure and CV events in patients with T2DM and albuminuric CKD.

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