CANVAS Program: Impact of Canagliflozin on CV and Renal Outcomes as per the Baseline Diuretic Use

13 May, 21

Introduction

The CANVAS program has established the cardiac benefits [primary and secondary prevention of heart failure (HF)] of canagliflozin in type-2 diabetes mellitus (T2DM) patients with established cardiovascular disease (CVD), chronic kidney disease (CKD) or those having albuminuria. Nevertheless, these benefits of canagliflozin treatment [in terms of reduction in major adverse cardiac effects (MACE)] varied as per the baseline use of diuretic therapy in patients. Assessing the safety profile of canagliflozin among patients taking baseline diuretics is thus important.

Aim

To elucidate the key clinical and safety outcomes associated with canagliflozin treatment as stratified by the baseline diuretic therapy

Patient Profile

Patients with T2DM [glycated hemoglobin (HbA1c) between ≥7% and ≤10.5%], and estimated glomerular filtration rate [(eGFR) >30 mL/min/1.73 m², n=10142]
The study participants either had a history of symptomatic atherosclerotic CVD (ASCVD; age ≥ 30 years) or were aged ≥50 years with ≥2 CV risk factors [T2DM duration of ≥10 years, systolic blood pressure (SBP) >140 mmHg while being treated with one or more antihypertensive agents, current smoker, microalbuminuria or macroalbuminuria, or high-density lipoprotein cholesterol (HDL-C) <38.67 mg/dL]
For this analysis, patients were stratified as per the baseline use of diuretics as follows:
- Any loop diuretics: furosemide, bumetanide, torsemide, piretanide, and ethacrynic acid
- Thiazide or Thiazide-like other diuretics: Any thiazides, altizide, chlorthalidone, clopamide, indapamide, metolazone, xipamide, and metipamide
- Mineralocorticoid receptor antagonists: MRAs; spironolactone and eplerenone
To further elucidate the association between baseline diuretic use and CV, renal and safety outcomes patients were also stratified as per the baseline diuretic use and ASCVD or HF

Methods

Study Design

A post hoc analysis of the CANVAS Program

The CANVAS Program comprised of 2 double-blind, randomized, placebo-controlled trials (CANVAS and CANVAS-R)

Treatment Strategy

The participants from the CANVAS program were randomized to canagliflozin or placebo

Outcomes

Primary Outcome

MACE, a composite of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke

Secondary Outcomes

Individual rates od CV death, fatal/ nonfatal MI, nonfatal stroke, or HF hospitalisation (HHF)
All-cause mortality
Composite renal outcomes (defined as a 40% reduction in eGFR requirement for renal replacement therapy, or renal death) and progression of albuminuria (defined as >30% increase in albuminuria and a change from either normoalbuminuria to microalbuminuria or macroalbuminuria or from microalbuminuria to macroalbuminuria)
Safety events (Serious and non-serious adverse events)

Follow-up

Mean period of 188 weeks

Results

Of the entire study population, 44.3% (n=4490) patients were using a diuretic at baseline. Patients using diuretics vs. those not using diuretics, were older, more likely female, and had HF (all P_difference <0.0001). Patients using diuretics at baseline also had a lower eGFR (P < 0.0001), higher SBP (P < 0.0001), and higher urinary albumin-to-creatinine ratio (P < 0.0001); when compared with patients not using diuretics at baseline.
Treatment with canagliflozin was associated with a greater reduction in the incidence of MACE in patients using diuretics at baseline vs. those not using diuretics (P_{heterogeneity}<0.0001).
This observed difference was mainly attributed to a risk reduction in non-fatal MI (P_{heterogeneity}=0.001). Similar heterogeneity was also observed for the incidence of CV death (P_{heterogeneity}=0.06) and non-fatal stroke (P_{heterogeneity}=0.07). There was no between-group heterogeneity for HHF (P_{heterogeneity}=0.58), albuminuria (P_{heterogeneity}=0.62), renal composite outcome (P_{heterogeneity}=0.23), or all-cause mortality (P_{heterogeneity}=0.37).
Canagliflozin was associated with a greater improvement in various CV risk factors such as; blood pressure, UACR, body weight, when compared with placebo, with no significant difference for patients using or not using diuretics at baseline.
The impact of canagliflozin on HbA1c reduction was slightly lower in patients using vs. not using diuretics at baseline (-0.52% vs.-0.64%, P_{heterogeneity}=0.0007).
Overall, there was no significant difference in the incidence of serious adverse events and key safety outcomes, including adverse renal events amongst patients using and not using diuretics at baseline (all P_{heterogeneity} >0.05).

Conclusions

Type-2 diabetes mellitus patients using diuretics at baseline gained greater clinical benefits in terms of reduced incidence of MACE with canagliflozin treatment when compared with patients not using diuretics at baseline.
Neither patient demographics nor the improvement in patient risk factor profile could explain this between group difference.
Canagliflozin treatment did not increase the incidence of overall AEs or renal AEs in patients on baseline diuretic therapy, indicating that concomitant use of canagliflozin and diuretics is safe.

ESC Heart Fail. 2021 Apr;8(2):1482-1493.