Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Abstract

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention).

Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care.

Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome).

Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02065791.

Keywords: canagliflozin; clinical trial; diabetes mellitus; primary prevention; renal insufficiency, chronic; secondary prevention.

Figures

Figure 1.

Effects of canagliflozin on cardiovascular outcomes in the overall population.A, Cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. B, Fatal or nonfatal myocardial infarction. C, Fatal or nonfatal stroke. D, Hospitalization for heart failure.

Figure 2.

Effects of canagliflozin on cardiovascular outcomes in the primary and secondary prevention cohorts.A, Cardiovascular death and hospitalization for heart failure. B, Cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

Figure 3.

Effects of canagliflozin on renal and cardiovascular outcomes in the secondary and primary prevention cohorts. eGFR indicates estimated glomerular filtration rate; and ESKD, end-stage kidney disease. *Diamonds represent the result of a single analysis of the full cohort. †The primary composite outcome included ESKD, doubling of serum creatinine, or renal or cardiovascular death. ‡Hazard ratios and 95% CIs were calculated for outcomes with >10 events. §The cardiovascular composite outcome included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or hospitalization for unstable angina. ‖Exploratory outcome.

Figure 4.

Effects of canagliflozin vs placebo on cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke across patient subgroups. BMI indicates body mass index; BP, blood pressure; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; and UACR, urine albumin:creatinine ratio. *Hazard ratios and 95% CIs were calculated for outcomes with >10 events.