Sodium‐glucose cotransporter 2 inhibitors for macroalbuminuria: A new indication

Abstract

A somewhat underappreciated cause of optimism has been the evidence from the cardiovascular outcome trials of type 2 diabetes (T2D) treatments that all the newer agents appear to improve aspects of renal function. The 2.6-year CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial randomizing 4401 persons with T2D, estimated glomerular filtration rate (eGFR) 30-90 mL/min/1.73m (mean baseline 56), and angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB)treated macroalbuminuria (>300 mg/g creatinine) to canagliflozin 100 mg daily or placebo showed highly significant reduction in renal disease outcomes, leading the US Food and Drug Administration on 27 September 2019 to add the following indication for the use of the agent: “to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria >300 mg/day.” This brief statement indicates a complete about-face from earlier assertions(currently included in the canagliflozin product information) that sodium-glucose transporter (SGLT)2 inhibitors are associated with elevation in serum creatinine and reduction in eGFR. In CREDENCE, the likelihood of doubling of serum creatinine with canagliflozin vs placebo was 4.3 vs 6.1 per 100 patient-years (hazard ratio 0.70 [95% confidence interval 0.59-0.82]), of decline in eGFR to <15 was 1.4 vs 2.2 (0.60 [0.45-0.80]), of cardiovascular death 1.9 vs 2.4 (0.78 [0.61-1.00]), and of heart failure hospitalization 1.6 vs 2.6 (0.61 [0.47-0.80]), with separation of the groups beginning to appear between 12 and 18 months. This new indication highlights the first drug class in nearly 20 years, since the ACEI and ARBs, to slow the progression of chronic kidney disease. We should ask: What is the implication for the treatment of T2D? Based on this report and similar evidence of renal protection with empagliflozin and dapagliflozin, which patients with diabetes should receive an SGLT2 inhibitor for a renal indication? In population studies of persons with diabetes, between one sixth and one third have albuminuria levels exceeding 30 mg/g creatinine. Only a minority of these persons have macroalbuminuria: in a Japanese population, 25% and 5% of persons with T2D had microand macroalbuminuria’; in Ramallah, Palestine, microand macroalbuminuria were present in 29% and 5%, respectively;in a population study in Turkey, microand macroalbuminuria were present in 43% and 9%, respectively; and in a similar study in Luxembourg, microand macroalbuminuria were present in 4% and 1%, respectively. Using data from cross-sectional studies of adults aged 20 years or older with diabetes mellitus participating in US National Health and Nutrition Examination Surveys from 1988 through 2014, the prevalence of microalbuminuria decreased from 16% in 1988-1994 to 11% in 2009-2014, with macroalbuminuria prevalence at 6% and 5% in the two time periods, and another study in Japan analyzed trends in albuminuria prevalence among T2D persons, showing a decline in microand macroalbuminuria prevalence from 29% and 13% in 1996, to 16% and 5% in DOI: 10.1111/1753-0407.13005