Evaluating the Effects of Canagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes Mellitus and Chronic Kidney Disease According to Baseline HbA1c, Including Those With HbA1c &lt;7%
Authors: Christopher P. Cannon, Vlado Perkovic, Rajiv Agarwal, James Baldassarre, George Bakris, David M. Charytan, Dick de Zeeuw, Robert Edwards, Tom Greene, Hiddo J.L. Heerspink, Meg J. Jardine, Adeera Levin, Jing-Wei Li, Bruce Neal, Carol Pollock, David C. Wheeler, Hong Zhang, Bernard Zinman, Kenneth W. Mahaffey
Journal: Circulation (2019)

canagliflozin ◼ chronic kidney disease ◼ diabetes mellitus, type 2 ◼ SGLT2 inhibitors T raditional management of diabetes mellitus has focused on glycemic control, beginning with lifestyle changes, followed by metformin, and then other classes of antiglycemic agents. 1 Sodium glucose co-transporter 2 inhibitors reduce cardiovascular events, including cardiovascular death, myocardial infarction, and heart failure, and slow the progression of renal dysfunction, including prevention of end-stage kidney disease. 2,3Because initial clinical trials included mostly patients with baseline HbA1c >7%, current guidelines have recommended this class of drugs as an add-on therapy for patients whose HbA1c is not at goal, typically ≥7%. 1 We hypothesized that there would be similar benefits on cardiovascular and renal end points regardless of baseline HbA1c, including those with HbA1c <7%.The CREDENCE trial (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) was a double-blind, randomized trial of canagliflozin 100 mg versus placebo in 4401 patients with type 2 diabetes mellitus and chronic kidney disease. 3As previously detailed, patients were eligible if they had an HbA1c level of 6.5% to 12.0%, an estimated glomerular filtration rate of 30 to <90 mL per minute per 1.73 m 2 of body-surface area and albuminuria (urinary albumin-to-creatinine ratio, >300 to 5000 mg/g). 3The study was approved by the necessary regulatory authorities and ethics committees, and participants provided written informed consent.Overall, canagliflozin significantly reduced the risk of the primary composite outcome (end-stage kidney disease, doubling of serum creatinine, or renal or cardiovascular death), as well as a renal composite outcome excluding cardiovascular death, major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), a composite of cardiovascular death and hospitalization for heart failure, and the standalone end point of hospitalization for heart failure.We analyzed cardiovascular, renal, and safety outcomes by baseline HbA1c and results are reported without adjustment for multiplicity.The distribution of patients by baseline HbA1c was <7% (N=650), 7% to <8% (N=1406), and ≥8% (N=2343) with mean values of 6.6%, 7.4%, and 9.2%, respectively.Baseline characteristics across the groups showed a mean age 64.1, 64.0, and 62.1 years; 26.9%, 31.3%, and 37.5% female; 49.5%, 49.3%, and 51.4% with history of atherosclerotic cardiovascular disease; mean duration of diabetes mellitus 14.7, 15.8, and 16.1 years; and mean estimated glomerular filtration rate 53.5, 54.8, and 57.8 mL/min/1.73m 2 , respectively.The difference in HbA1c at 13 weeks between canagliflozin and placebo was -0.18%, -0.23%, and -0.40%, respectively.Across categories of baseline HbA1c, treatment with canagliflozin resulted in similar risk reductions of the primary composite outcome, cardiovascular death,