Canagliflozin trial shows positive renal and cardiovascular outcomes
Canagliflozin trial shows positive renal and cardiovascular outcomes
- Patients with type 2 diabetes are at high risk of kidney disease
- Canagliflozin was found to reduce risk of kidney disease and other renal outcomes compared with placebo
- Canagliflozin also improves CV outcomes compared with placebo
The incidence of kidney disease has increased significantly over recent years and is predicted to continue to rise, a trend primarily driven by the concomitant increase in prevalence of type 2 diabetes (T2D). No treatments have been granted approval for renoprotection in patients with T2D since renin-angiotensin system blockade in 2001. Exploratory analyses of trials with sodium-glucose co-transporter 2 (SGLT-2) inhibitors have suggested some renal benefit, however, due to low numbers of patients at high risk of kidney failure, further work was warranted.
Study designThe CREDENCE trial was introduced by Professor Carol Pollock, Nephrologist, Sydney University, Australia at the 2019 EASD annual meeting. CREDENCE was a double-blind, randomised phase III trial designed to test renal and cardiovascular (CV) outcomes in patients with T2D treated with canagliflozin. Patients eligible to take part had T2D and albuminuric chronic kidney disease, with an estimated glomerular filtration rate (eGFR) of 30 to <90 mL/min/1.73m2 of body surface area, albuminuria (defined as albumin (mg): creatine (g) ratio of >300 to 5,000) and were being treated with renin-angiotensin system blockade. 4,401 patients from 690 sites in 34 countries were randomised and received either 100 mg canagliflozin or placebo once daily.
- Composite of end-stage kidney disease (ESKD, ie dialysis, transplantation or sustained eGFR of <15mL/min/1.73m2), a doubling of serum creatinine level, or death from renal or CV causes
- A series of prespecified secondary outcomes were tested hierarchically, including composite and individual CV and renal outcomes
Main outcomesThe trial was stopped early on the recommendation of the data monitoring committee, when it was found at the interim analysis that the prespecified efficacy data had been achieved. The median follow-up time was 2.62 years (range: 1 week to 4.53 years).
Professor Hiddo Lambers Heerspink, Clinical Pharmacologist, University of Groningen, the Netherlands described the main intermediate outcomes and renal outcomes from the trial. The group treated with canagliflozin showed a significantly lower rate of the events defined by the primary composite (ESKD, doubling of serum creatinine, or renal or CV death), which occurred for 245 participants for canagliflozin compared with 340 for placebo (HR 0.70; 95% CI 0.59 to 0.82; p=0.00001).
Over the course of the study (42 months), compared with placebo, canagliflozin reduced:
- HbA1c by -0.25% (baseline mean: 8.3%; 95% CI -0.20 to -0.31)
- systolic blood pressure by -3.30 mmHg (baseline mean: 140 mmHg; 95% CI -2.73 to -3.87)
- urea albumin: creatinine ratio by -32% (baseline mean: 927 mg/g; 95% CI -28 to -36)
- bodyweight by -0.80 kg (95% CI -0.69 to -0.92)
Improvements in these factors would be expected to result in renoprotection.
Renal outcomesThe renal-specific composite outcome of ESKD, doubling of serum creatinine, or renal death occurred in 153 participants in the canagliflozin group compared with 224 participants in the placebo group (HR 0.66; 95% CI 0.53 to 0.81; p<0.001). Canagliflozin was also seen to improve the following renal outcomes compared with placebo:
- ESKD: 116 vs 165 participants (HR 0.68; 95% CI 0.54 to 0.86, p=0.002)
- Doubling of serum creatinine level: 118 vs 188 participants (HR 0.60; 95% CI 0.48 to 0.76; p<0.001)
- Composite of dialysis, kidney transplantation, or renal death: 78 vs 105 participants (HR 0.72; 95% CI 0.54 to 0.97; post hoc analysis)
The results were further compared for subgroups of the patients based on kidney function (ie difference in eGFR or baseline urinary albumin: creatinine ratio). Both the primary composite outcome and a renal composite outcome were similar across patients with different severity of kidney disease, including those individuals with baseline eGFR of 30 to <45 mL/min/1.73m2. Results were also consistent when analysed by sex, age (</≥65 years), baseline BMI (</≥30 kg/m2), baseline HbA1c (</≥8%) and baseline systolic blood pressure (≤/> median).
Cardiovascular outcomesThe CV outcomes of CREDENCE were presented by Professor Kenneth Mahaffey, Cardiologist, Stanford University, US. The risks of the following CV outcomes were significantly reduced in the group treated with canagliflozin compared with the placebo group:
- Composite of CV death or hospitalisation for heart failure: 179 vs 253 participants (HR 0.69; 95% CI 0.57 to 0.83; p<0.001)
- Composite of CV death, myocardial infarction or stroke: 217 vs 269 participants (HR 0.80; 95% CI 0.67 to 0.95; p=0.01)
- Hospitalisation for heart failure: 89 vs 141 participants (HR 0.61; 95% CI 0.47 to 0.80; p<0.001)
There was a numerical but not statistically significant difference between the groups in the risk of CV death: 110 vs 140 participants (HR 0.78; 95% CI 0.61 to 1.00; p=0.05).
Safety outcomesThere were no significant differences in the rates of adverse events or serious adverse events between the canagliflozin and placebo groups. Both the risk of lower-limb amputation and the risk of fracture was similar between the two groups. The incidence of diabetic ketoacidosis was low overall, but was significantly higher in the canagliflozin-treated group than the placebo group (2.2 and 0.2 per 1,000 patient-years, respectively).
Conclusions30-40% of patients with T2D will develop chronic kidney disease. The patients in the CREDENCE trial were at a higher renal risk compared with patients in previous trials with other SGLT-2 inhibitors (dapagliflozin in DECLARE, canagliflozin in CANVAS, empagliflozin in EMPA-REG). The results showed clear evidence of canagliflozin providing protection against kidney failure in this population, as well as against heart failure and CV disease.
Based on the "CREDENCE" session held on Tuesday 17 September 2019 at the 55th Annual Meeting of the European Association for the Study of Diabetes (EASD), Barcelona, Spain, 16-20 September 2019:
Pollock C. Introduction and design (OP SO4.1); Heerspink H L. Renal outcomes (OP SO4.2); Mahaffey K. Cardiovascular and safety outcomes (OP SO4.3); Nauck M A. Commentary (OP SO4.4).
BMI: body mass index; CI: confidence interval; CV: cardiovascular; eGFR: estimated glomerular filtration rate; ESKD: end-stage kidney disease; HR: hazard ratio; SGLT-2: sodium-glucose co-transporter 2; T2D: type 2 diabetes.
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