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Canagliflozin reduces major cardiovascular events and kidney failure in patients with type 2 diabetes and chronic kidney disease


Results of a new subgroup analysis from the phase 3 CREDENCE study, showing Canagliflozin ( Invokana ) has significantly reduced the risk of major cardiovascular ( CV ) events and kidney failure in patients with type 2 diabetes ( T2D ) and chronic kidney disease ( CKD ), were presented at the American Diabetes Association's 79th Scientific Sessions.
These positive results were observed in patients taking Canagliflozin, including those with cardiovascular risk factors but no history of cardiovascular disease ( primary prevention group ) and patients with history of cardiovascular disease, defined as a history of coronary, cerebrovascular or peripheral vascular disease ( secondary prevention group ).

Published in The New England Journal of Medicine ( NEJM ), the phase 3 CREDENCE study has evaluated cardiovascular and renal outcomes in patients with T2D and CKD taking either Canagliflozin or placebo, in addition to standard of care.

For the new subgroup analysis presented at ADA ( American Diabetes Association ), CREDENCE researchers specifically examined cardiovascular and renal outcomes in the primary prevention group ( n=2,181; 49.6% ) and secondary prevention group ( n=2,220; 50.4% ).
Compared to secondary prevention participants, primary prevention participants were younger ( 61.4 vs. 64.6 years ) and more often female ( 36.6% vs. 31.3% ), but with similar T2D duration ( 15.2 vs. 16.4 years ).

The cardiobascular results from CREDENCE found Canagliflozin has significantly reduced major cardiovascular events in the overall study population, with consistent results across all composite endpoints and individual components of the composite endpoints.
Specifically, Canagliflozin has reduced the risk of cardiovascular death, myocardial infarction or stroke by 20% compared to placebo ( 9.9% vs. 12.2%; hazard ratio [ HR ]: 0.80; 95% confidence interval [ CI ]: 0.67 to 0.95; P=0.01 ).
Canagliflozin has also reduced the risk of cardiovascular death or hospitalization for heart failure by 31% ( 8.1% vs. 11.5%; HR: 0.69; 95% CI: 0.57 to 0.83; P less than 0.001 ) and hospitalization for heart failure by 39% ( 4.0% vs. 6.4%; HR: 0.61; 95% CI: 0.47 to 0.80; P less than 0.001 ).

For the subgroup analysis, researchers found:

a) cardiovascular results observed in the overall study population were consistent across the primary and secondary prevention groups, including all clinical subgroups and across groups defined by renal function;

b) for cardiovascular death, myocardial infarction and stroke, there was no evidence of heterogeneity between the primary and secondary prevention groups ( p-interaction=0.25 ). Specifically, Canagliflozin has reduced the risk of the composite of cardiovascular death, myocardial infarction and stroke by 32% in the primary prevention group ( HR: 0.68; 95% CI, 0.49 to 0.94 ) and 15% in the secondary prevention group ( HR: 0.85; 95% CI, 0.69 to 1.06 ).

The renal results from CREDENCE found Canagliflozin has demonstrated a 30% reduction in the risk of the primary composite endpoint, comprised of progression to doubling of serum creatinine, end-stage renal disease ( ESKD ), and renal or cardiovascular death ( HR: 0.70; 95% CI: 0.59 to 0.82; P less than 0.0001 ) – with consistent results across individual components of the primary composite endpoint, as well as across all 15 prespecified subgroups examined.

For the subgroup analysis, researchers found:

a) Renal results observed in the overall study population were consistent across the primary and secondary prevention groups;

b) Specifically, Canagliflozin has reduced the risk of ESKD by 31% ( HR: 0.69; 95% CI: 0.51 to 0.95; P-interaction: 0.89 ) and 33% ( HR: 0.67; 95% CI: 0.47 to 0.96; P-interaction: 0.89 ) in the primary and secondary prevention groups, respectively.

In addition, CREDENCE found the incidence rates of adverse events and serious adverse events were numerically lower for patients treated with Canagliflozin as compared to placebo.
For the subgroup analysis, safety outcomes were similar in both primary and secondary prevention groups.
There was no difference in fracture risk or incidence of amputations in the primary and secondary prevention groups.

CREDENCE ( Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation ) clinical trial was a randomized, double-blind, event-driven, placebo-controlled, parallel-group, two-arm, multicenter study. It evaluated 4,401 patients from 34 countries with T2D and established stage 2 or 3 CKD who were receiving standard of care, which included a maximum tolerated labeled daily dose of angiotensin-converting enzyme ( ACE ) inhibitors or angiotensin II receptor blockers ( ARBs ).
Patients were randomized in a 1:1 ratio and received either Canagliflozin 100 mg daily or matching placebo, with a mean follow-up of 2.62 years.( Xagena )

Source: Janssen, 2019

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