CREDENCE: The Impact of Canagliflozin on HF and CV Death as per the Baseline Patient Characteristics

29 Apr, 21

Introduction

Type-2 diabetes mellitus (T2DM) patients with chronic kidney disease (CKD) frequently have co-existing heart failure (HF), which in turn is associated with increased morbidity and mortality. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial has already demonstrated a significant 31% reduction in the risk of hospitalization for HF (HHF) or cardiovascular (CV) death in patients with T2DM and CKD. It is not known whether this benefits of canagliflozin would vary as per the baseline characteristics of the patients.

Aim

To determine whether the effect of canagliflozin on HHF/CV death varied as per the subgroups defined by key baseline patient characteristics associated with incident HF and the associated complications

Patient Profile

Type-2 diabetes mellitus patients aged ≥30 years, with a glycosylated hemoglobin (HbA1c); 6.5%-12.0%, and CKD, defined as an estimated glomerular filtration rate (eGFR) of 30 to less than 90 mL/min/1.73m²and a urinary albumin-to-creatinine ratio (UACR) of more than 300 to 5000 mg/g
All patients received maximum tolerated dose of renin angiotensin system blockade minimum of four weeks before randomization

Methods

Study Design

A sub-study of the CREDENCE trial
CREDENCE was an event-driven, double-blind, randomized control trial

Treatment Strategy

Patients underwent 2-week single-blind placebo run-in period before randomization
Patients were randomized to canagliflozin (100 mg) or placebo

Patient Categorization

Patients were categorized further, based on the following baseline characteristics:
- Baseline eGFR: 30 to <45, 45 to <60 and 60 to <90 mL/min/1.73m²
- Age: (<65 or ≥65 years)
- Gender: Male or female
- Race: White, Asian, Black, other
- History of CV disease [(CVD); symptomatic atherosclerotic vascular disease]: Yes/no
- History of HF [none, yes, New York Heart Association (NYHA) class I, II or III)
- History of hypertension: Yes/no
- History of atrial fibrillation (AF): Yes or no
- UACR category: ≤1000 or >1000 mg/g
- Baseline HbA1c category: <8% or ≥8%
- Body mass index category: ≤25, 25–<30, ≥30 kg/m²
- Duration of diabetes (≤10, >10 years)
- Use of diuretics: Yes or no
- Use of glucagon-like peptide-1 (GLP-1) receptor agonists: Yes or no
- Use of metformin: Yes or no

Outcomes

Hazard ratio (HR) and absolute risk difference for incident HF and its complications in patients treated with canagliflozin vs. placebo.

Follow-up Visits

Weeks 3, 13 and 26, followed by alternate clinic and telephone follow-up at 13-week interval thereafter

Follow-up

Median duration; 2.62 years

Results

The mean age of the study population was 63 years. Of the entire study population, 34% were females, 15% had a history of HF and 50% had a history of CVD at baseline. The baseline characteristics were similar in both the study groups.
Patients who experienced HHF/CV death vs. those who did not, were older, and more probably had a history of HF, CVD or AF, had a higher UACR, HbA1c, systolic blood pressure (SBP) and lower eGFR at study baseline (Table 1).

Table 1: Baseline characteristics stratified by occurrence of composite outcome

Characteristic	Patients who experienced HHF/CV death	Patient who did not experience HHF/CV death	P value
Age	65.3 years	62.8 years	<0.001
History of HF	26.9%	13.5%	<0.001
History of CVD	65.3%	48.8%	<0.001
History of AF	9.7%	4.8%	<0.001
UACR	1265 mg/g	884 mg/g	< 0.001
HbA1c	8.4%	8.2%	0.004
SBP	141.8 mmHg	139.8 mmHg	0.01
eGFR	51.8 mL/min/m²	55.0 mL/min/m²	< .001

Treatment with canagliflozin was significantly reduced the risk of composite outcome of HHF/CV death in patients with T2DM and CKD regardless of age (p_interaction = 0.509), gender (p_interaction = 0.747), history of HF (p_interaction = 0.236) or history of CVD (p_interaction = 0.566).
The benefits of active treatment were also evident irrespective of baseline eGFR (p_interaction = 0.567), UACR (p_interaction = 0.590) and the use of loop diuretics (p_interaction = 0.246), GLP-1 receptor agonists (p_interaction = 0.585) or metformin (p_interaction = 0.557).
Patients with a history of CVD, a history of HF, lower eGFR and higher UACR had an increased risk of HHF/CV death. Accordingly, the absolute benefits of canagliflozin treatment in these groups were greater than those evident in patients with a lower background risk.

Conclusions

Type-2 diabetes mellitus patients with co-existing CKD are at an increased risk of HHF/CV death event. Treatment with canagliflozin was associated with a consistent reduction in the proportional risk of these events across a broad range of patient subgroups.
The absolute benefit of canagliflozin was greater in patients at highest risk, for example in patients with a history of CV disease or advanced kidney disease.

Diabetes Obes Metab. 2021 Mar 26 (Online ahead of print); doi: 10.1111/dom.14386.