Over the last five years, several oral glucose-lowering medications for type 2 diabetes have been found to improve more than just hemoglobin A1c, with reduction in cardiovascular events and cardiovascular mortality also being shown. The just-published CREDENCE trial examined the effects of the sodium glucose cotransporter 2, canagliflozin, on cardiovascular and renal complications of type 2 diabetes. Over 4,000 patients with stage II or III chronic kidney disease and albuminuria were randomized to either canagliflozin 100 mg daily or placebo. All patients were on an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at maximum tolerated dose. The primary outcome was a composite of doubling of creatinine, end-stage renal disease (defined as need for dialysis, kidney transplant, or estimated GFR < 15 mL/min/1.73 m2), and death from cardiovascular or renal cause. Participants had an average age of 63 years, average HbA1C 8.3%, and 50% in each group had cardiovascular disease. At the start of the trial, participants in both the canagliflozin and placebo groups had similarly high rates of drug therapy, including use of insulin, biguanide, and statins. Over 65% of patients in each group were white, with only 5.1% identifying as black or African American.
The trial ended early when a prespecified efficacy endpoint was met after 2.6 years of follow-up. The primary composite outcome occurred in 11.1% of patients receiving canagliflozin compared to 15.4% receiving placebo (hazard ratio [HR] 0.7, 95% CI 0.59-0.82). This reduction was primarily driven by the doubling of serum creatinine outcome. The composite of end-stage kidney disease (a component of the primary composite outcome) was also significantly lower in patients receiving canagliflozin (HR 0.68, 95% CI 0.54-0.86), but this was mainly due to a significant reduction in patients with GFR < 15; there was no significant difference in need for dialysis or kidney transplant. The majority of secondary outcomes were also reported as composites, sometimes composites within composites. Patients receiving canagliflozin had significant reduction in the composite outcomes of cardiovascular death or hospitalization for heart failure; cardiovascular death, myocardial infarction, or stroke; and cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure or unstable angina. The only components reported independently were cardiovascular death (nonsignificant) and hospitalization for heart failure (lower in patients receiving canagliflozin, HR 0.61, 95% CI 0.47-0.80). Rates of death from any cause and renal death were not statistically significant between groups.
Estimating the true benefit of SGTL2 inhibitor therapy is challenging when a multitude of composite outcomes are presented as favorable, yet the net benefit may be minimal in terms of patient-oriented outcomes. While doubling of creatinine makes for a good headline, this is a surrogate marker and may not represent need for dialysis or transplant. These results must also be considered in the context of evidence that canagliflozin may increase the risk of acute kidney disease, amputations, and Fournier’s gangrene. Overall, canagliflozin appears to offer a small but consistent cardiovascular benefit, but these data don’t seem to suggest that it’s the next ACE inhibitor in terms of renal protection for patients with diabetes.
DynaMed Plus EBM Focus Editorial Team
This EBM Focus was written by Carina Brown, MD, Faculty Development and Information Mastery Fellow and Clinical Instructor at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed Plus and Associate Professor in Family Medicine at the University of Massachusetts Medical School and Katharine DeGeorge, MD, MS, Assistant Professor in Family Medicine at the University of Virginia and Clinical Editor at DynaMed Plus.