PracticeUpdate Diabetes June 2019

EDITOR’S PICKS 7

Canagliflozin Improves Renal Outcomes in Type 2 Diabetes The New England Journal of Medicine

Take-home message • In this study, 4401 patients with type 2 diabetes and albuminuric chronic kidney disease were randomized to receive canagliflozin or placebo to investigate renal outcomes. At a median follow-up of 2.62 years, the relative risk of a composite of end-stage kidney disease, a doubling of the serum creatinine level, and death from renal or cardiovascular disease was 30% lower in patients receiving canag- liflozin compared with placebo. These patients also had a significantly lower risk of cardiovascular death, myocardial infarction and stroke, and a significantly lower risk of hospitalization for heart failure. • These findings demonstrate that canagliflozin treatment leads to a lower risk of kidney failure and cardiovascular events in patients with type 2 diabetes and kidney disease.

Abstract BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are avail- able. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), explor- atory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m 2 of body-sur- face area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2 ), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommenda- tion of the data and safety monitoring committee. At that time, 4401 patients had undergone ran- domization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kid- ney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitali- zation for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the can- agliflozin group than in the placebo group at a median follow-up of 2.62 years. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019 Apr 14;[EPub Ahead of Print], V Perkovic, MJ Jar- dine, B Neal, et al. www.practiceupdate.com/c/82411

COMMENT By Steven G. Coca DO, MS T he CREDENCE trial results provide a major accomplishment for patients with diabetic kidney disease (DKD) and for nephrology. Since the IDNT and RENAAL trials of angiotensin receptor blockers were published in 2001, there had not been a single positive phase III clinical trial of any new agent – including bardoxolone (BEACON), sulodexide (Sun-MACRO), aliskiren (ALTITUDE) – or strategies (dual RAAS blockade [VA NEPHRON-Daswell as theaforementioned ALTITUDE trial]) in patients with DKD. CREDENCE enrollment began in 2014, and, in the intervening time, there has been simmering hope for patients with DKD. In the EMPA-REG Outcome, CANVAS Program, and DECLARE TIMI- 58 trials, there were strong signals for kidney protection in patients with type 2 diabetes and high cardiovascular risk. 1-3 Kidney-related endpoints were reduced by 40% to 50% in these three large trials of different SGLT2 inhibitors. In these three trial populations, however, the baseline eGFR was 74 to 85 and median UACR was 12 to 18 mg/g. Only 9% to 26% of participants had a baseline eGFR <60 and only 7% to 11% had UACR >300 mg/g. Thus, although there was optimism for this class, there was still trepidation of how the SGLT2 inhibitors would fare in patients with overt DKD (UACR >300 mg/g). The CREDENCE results did not disap- point. The effect sizes for canagliflozin versus placebo were robust for every

kidney-related outcome (and cardiovas- cular outcomes). In fact, the consistency in the effect sizes across the SGLT2 inhibitor trials, the lack of interactions by baseline characteristics, including baseline eGFR or albuminuria, the flattening of eGFR slopes over time, and the lack of a consist- ent signal for significant adverse events suggest none other than the following statement: SGLT2 inhibitors represent a “game-changing” breakthrough therapy in patients in early and later phases of type 2 diabetes for safely reducing the risk of inci- dent and prevalent kidney disease. References 1. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375(4):323-334. 2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377(7):644-657. 3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380(4):347-357. Dr. Coca is Associate Chair for Clinical and Translational Research, Department of Internal Medicine and Associate Professor of Medicine at Icahn School of Medicine in Mount Sinai, New York. later phases of type 2 diabetes for safely reducing the risk of incident and prevalent kidney disease. " " SGLT2 inhibitors represent a ‘game-changing’ breakthrough therapy in patients in early and

VOL. 3 • NO. 2 • 2019