CANVAS Program: Impact of Canagliflozin on Cardiovascular and Renal Outcomes in Type-2 Diabetes Patients

Background

Type-2 diabetes mellitus (T2DM) patients are burdened with a substantial risk of cardiovascular (CV) and renal disease. Canagliflozin, a sodium–glucose co-transporter-2 (SGLT2) inhibitor reduces glycemia along with a reduction in blood pressure and body weight in type 2 diabetes patients. Canagliflozin also has a favorable impact on intra-renal hemodynamics and albuminuria.

Aim

The CANVAS (The Canagliflozin Cardiovascular Assessment Study) Program (an integrated analysis of CANVAS and CANVAS-Renal [CANVAS-R] studies) aimed at evaluating the impact of canagliflozin treatment on CV, renal, and safety outcomes in T2DM patients at high risk for cardiovascular disease.

Patient Profile

• Adults with T2DM (glycated hemoglobin [HbA1c]; ≥7% to ≤10.5%) and at high risk of cardiovascular disease (CVD)
• Patients aged ≥30 years with a history of symptomatic CVD or those aged ≥50 years with at least two of the following CVD risk factors:
  • Duration of diabetes ≥10 years
  • Systolic blood pressure (SBP) >140 mm Hg while receiving ≥1 antihypertensive agents
  • Current smoking
  • Microalbuminuria or macroalbuminuria,
  • High-density lipoprotein-cholesterol (HDL-C) level <38.7 mg/dL (1 mmol/L)
• Baseline estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m² of body surface area.

Methods

Study Design

• Randomized double-blind study with a 2-week placebo run-in phase

Treatment Strategy

• Participants from CANVAS study were randomized in 1:1:1 ratio and those from the CANVAS-R in 1:1 ratio to receive canagliflozin or placebo

Follow-Up

• CANVAS Program - mean follow-up: 188.2 weeks
  • CANVAS – mean follow up: 295.9 weeks
  • CANVAS-R – mean follow up: 108 weeks

Outcomes

Primary Outcome

• A composite of death from CV causes, nonfatal myocardial infarction (MI), or nonfatal stroke

Secondary Outcomes

• Death from any cause
• Death from CV causes
• Progression of albuminuria (defined as: a >30% increase in albuminuria and a change from either normoalbuminuria to microalbuminuria/ macroalbuminuria or from microalbuminuria to macroalbuminuria
• The composite of death from CV causes and hospitalization for heart failure

Exploratory Outcomes

Prespecified Cardiovascular Outcomes

• Nonfatal MI
• Nonfatal stroke and
• Hospitalization for heart failure

Prespecified Renal Outcomes

• Regression of albuminuria, and the renal composite comprising a 40% reduction in eGFR sustained for at least two consecutive measures, the need for renal-replacement therapy (dialysis or transplantation), or death from renal causes

Safety Analysis

• Any adverse events

Results

• A total of 96% (n=9734) individuals completed the trial. The mean age of the study subjects was 63.3 years and 35.8% were women. The mean duration of diabetes was 13.5 years, and 65.6% subjects had a history of cardiovascular disease CVD at baseline.
• The incidence of primary outcome was significantly lower in the canagliflozin group vs. the placebo group; a 14% risk reduction in the primary outcome was observed with canagliflozin vs placebo (P<0.001 for noninferiority, P=0.0158 for superiority (Table1)
• The reductions in incidence of fatal secondary outcome including death from any cause, and death from CV causes was statistically non-significant in both the study groups
• Canagliflozin demonstrated a 33% significant reduction in hospitalization due to heart failure as well as a 22% reduction in a composite outcome of CV death or hospitalization due to heart failure
• A 27% reduction in progression of albuminuria and a 70% increase in regression of albuminuria was observed with canagliflozin-treated patients vs. the placebo-treated patients.
• The incidence of renal composite outcome comprising of sustained 40% reduction in eGFR, the need for renal-replacement therapy, or death from renal causes was less frequent in the canagliflozin group vs. the placebo group; a 40% reduction was observed with canagliflozin vs. placebo for this composite outcome (Table 1)

• Dose of canagliflozin was increased to 300 mg in 71.4% of CANVAS-R participants. All study subjects were treated appropriately with other medications for glycemic control and CV risk.
• The use of other antidiabetic medications during follow-up was 9.3% lower in the group treated with canagliflozin vs. group receiving placebo.
• Over the entire follow-up period, canagliflozin demonstrated greater HbA1c (-0.58%), body weight (-1.6 kg) and SBP (-3.93 mm Hg) reductions compared to placebo (P<0.001 for all comparisons)
• Canagliflozin-treated patients had an increase in HDL-C (2.05 mg/dL) as well as LDL-C (4.68 mg/dL) vs. placebo group. However, the LDL-C to HDL-C ratio remained unchanged
• The incidence of serious adverse events was less frequent in the canagliflozin group vs. placebo group (104.3 vs. 120.0 participants with an event per 1000 patient-years; HR 0.93)
• A higher risk of amputation, although of very low incidence (6.3 vs. 3.4 participants with amputation per 1000 patient-years; HR 1.97) was observed with canagliflozin compared to placebo. Majority of the amputations (71%) occurred at the level of the toe or metatarsal. The highest absolute risk of amputation was observed in patients with a history of amputation or peripheral arterial disease, but relative risk with canagliflozin vs. placebo was similar across these subgroups.
• Canagliflozin did not increase the risk of hypoglycemia, hyperkalemia, acute kidney injury, pancreatitis, malignancies, or venous thromboembolism vs. placebo
• The incidence of all fractures was higher in the canagliflozin group vs. the placebo group (15.4 vs. 11.9 participants with fracture per 1000 patient-years; HR 1.26). A similar trend was observed for low-trauma fractures events as well (11.6 vs. 9.2 participants with fracture per 1000 patient-years; HR 1.23 non-significant). Further, low-trauma fracture incidence was higher in canagliflozin group vs. placebo in CANVAS but not in CANVAS-R.
• The incidence of ketoacidosis was less frequent in both, canagliflozin and placebo groups (0.6 vs. 0.3 participants with an event per 1000 patient years; HR 2.23)

Conclusions

• When added to the current standard of care, canagliflozin further lowered the risk of CV events in T2DM patients at high risk of CVD
• Canagliflozin also demonstrated reduction in renal outcomes
• Canagliflozin treatment was associated with a higher risk of amputation, although of very low incidence, compared to current standard of care

N Engl J Med. 2017; 377: 644 - 57