PracticeUpdate Diabetes Best of 2018

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Canagliflozin and Renal Outcomes in Type 2 Diabetes By Deborah Wexler MD, MSc T ype 2 diabetes and hypertension are the most common causes of chronic kidney disease (CKD), and almost half of people with CKD have

death from renal causes was reduced by 47% in the canagliflozin compared with the placebo group (abso- lute risk reduction of 1.3 events per 1000 patient-years). Each of the elements of the composite renal outcome were clinically and statistically significantly reduced with the exception of ESRD, or death from renal dis- ease. These had hazard ratios favoring canagliflozin with confidence intervals crossing 1, with a small num- ber of events for these outcomes limiting power. As was seen in EMPA-REG, annual eGFR decline was slower in the canagliflozin arm. Similarly, UACR was lower at the end of the trial in the canagliflozin arm compared with the placebo arm, whereas renal-related adverse events were similar. Effects were largely, but not uniformly, consistent across subgroups, including among those with eGFR >60 mL/min and without ele- vation in UACR at baseline, and among those currently treated with RAAS blockade. This report was quickly followed in July 2018 by a press release announcing that the CREDENCE trial, which specifically tested the hypothesis that canagliflozin was beneficial for patients with type 2 diabetes melli- tus, eGFR >30–90, and UACR >300 mg/g treated with RAAS, was stopped early for efficacy. DECLARE–TIMI 58, the cardiovascular outcomes trial of dapagliflozin, will be reported at the American Heart Association Scientific Sessions in November 2018 and is likely to report renal outcomes as well. Numerous other SLGT2 inhibitor studies are ongo- ing, and we still lack long-term follow-up data on large cohorts of patients because these medications were introduced to the market over the last 5 years. Nonetheless, if these results are borne out in pend- ing trials, it is likely that the availability of a class of medications that have glucose-lowering and renopro- tective effects in addition to their other benefits will likely shift the paradigm of care for people with type 2 diabetes. Furthermore, the ongoing studies, Dapa-CKD and EMPA-Kidney, using dapagliflozin and empagli- flozin, are currently recruiting patients with CKD who do not have diabetes. When these report, we will learn whether the benefits of this class extend to the gen- eral CKD population as well. References 1. The National Institute of Diabetes and Digestive and Kidney Diseases. Kidney disease statistics for the United States. Published December 2016. 2. Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol 2018;6(9):691-704. 3. 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. www.practiceupdate.com/c//76124

diabetes. Rates of incident end-stage renal disease have leveled off and then declined recently thanks to advances in blood pressure management (including use of ACE inhibitors or angiotensin receptor block- ers, together called renin–angiotensin–aldosterone system [RAAS] blockade), glycemic control, and statin use. However, there is very high residual risk, with little in the way of new therapy for CKD prevention or treat- ment beyond the measures noted above. 1 One of the biggest stories of 2018, “Canagliflozin and Renal Outcomes in Type 2 Diabetes,” 2 strengthened the evidence base that the SGLT2 inhibitors, devel- oped for management of hyperglycemia in type 2 diabetes, represent a new tool in the therapeutic armamentarium for patients with type 2 diabetes and CKD. This was believed to be the case based on renal phys- iologic effects of SGLT2 inhibitors on renal glomerular function, and it was supported by findings from the EMPA-REG OUTCOME randomized controlled trial. In EMPA-REG, empagliflozin showed an absolute risk reduction of 6.1% in the composite renal outcome of progression to macroalbuminuria (>300 mg/g urinary albumin-to-creatinine ratio [UACR]), doubling of serum creatinine, initiation of renal replacement therapy, and death from renal disease and incident albuminu- ria (>30 mg/g UACR), but renal outcomes were not adjudicated. 3

" …if these results are borne out in pending trials, it is likely that the availability of a class of medications that have glucose-lowering and renoprotective effects in addition to their other benefits will likely shift the paradigm of care for people with type 2 diabetes. "

For many of the cardiovascular outcomes trials in dia- betes, heterogeneous effects for some outcomes have been observed across different medications within a class and across trials. The publication of the CAN- VAS renal outcomes paper in June 2018 strengthened the finding that the effect of SGLT2 inhibitors on renal function is likely a class effect. The CANVAS program studied canagliflozin and is comprised of two differ- ent trials: CANVAS and CANVAS-R, which enrolled 10,142 participants with mean baseline HbA1c 8.3%, eGFR 76 mL/min, and median UACR 12.3 mg/g, 80% of whom were prescribed RAAS blockade. Renal out- comes were adjudicated. The composite outcome of sustained doubling of serum creatinine, ESRD, and

VOL. 2 • NO. 4 • 2018