Flozins for the Kidneys Too

Published - Written by Angela Chen, MBBS, MPH

Susan is a 68-year-old woman with a long-standing history of type 2 diabetes. She has multiple microvascular and macrovascular complications, including diabetic nephropathy. For the last 5 years, Susan’s medication regimen has consisted of metformin, insulin, an angiotensin-converting-enzyme (ACE) inhibitor for blood pressure control and renoprotection, and a statin to manage her cholesterol levels. Recently, Susan heard from one of her friends about a diabetes medication that can protect her kidneys too. She asked her primary care physician if she would benefit from this medication. 

Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood-glucose levels and cardiovascular risk in patients with type 2 diabetes. The initial cardiovascular outcome trials that evaluated the safety of the SGLT2 inhibitors indicated that they might also have renoprotective effects. However, the original studies were not powered to evaluate this outcome.

In a randomized, placebo-controlled study recently published in the NEJM, Perkovic et al. examined the effect of the SGLT2 inhibitor, canagliflozin, on renal outcomes in a trial of 4400 patients with type 2 diabetes and impaired renal function. Renal impairment was defined as glomerular filtration rate between 30–90 ml/minute/1.73m2 and urinary albumin-to-creatinine ratio between 300–5000. The investigators found that canagliflozin use was associated with improved renal outcomes in patients with type 2 diabetes and renal impairment. In patients like Susan, use of SGLT2 inhibitors is likely to offer additional renoprotective benefits.

The following NEJM Journal Watch summary further explains the study and findings:


Renoprotection with Canagliflozin

Allan S. Brett, MD reviewing Perkovic V et al. N Engl J Med 2019 Apr 14 Ingelfinger JR and Rosen CJ. N Engl J Med2019 Apr 14

In a randomized trial, this drug significantly lowered the rate of adverse renal outcomes in type 2 diabetic patients.

The sodium–glucose cotransporter 2 inhibitor canagliflozin (Invokana) is FDA-approved to lower cardiovascular (CV) risk in patients with type 2 diabetes and established CV disease. Now, industry-supported researchers have examined the drug's effect on renal outcomes in 4400 patients with type 2 diabetes. Enrollment criteria included estimated glomerular filtration rate between 30 and 90 mL/minute/1.73 m2 (mean, 56) and urinary albumin-to-creatinine ratio between 300 and 5000. Mean age was 63 and mean glycosylated hemoglobin (HbA1c) level was 8.3%; 66% of patients were taking insulin, and 58% were taking metformin.

Patients were randomized to receive either canagliflozin or placebo. At median follow-up of 2.6 years, the primary composite outcome (end-stage renal disease [ESRD], doubling of serum creatinine, renal-related death, or CV-related death) occurred significantly less frequently with canagliflozin than with placebo (11.1% vs. 15.5%). Outcomes for components of this endpoint consistently favored canagliflozin over placebo: 5.3% vs. 7.5% for ESRD, 5.3% vs. 8.5% for doubling of creatinine, and 5.0% vs. 6.4% for CV-related death. Only a few renal-related deaths occurred. Canagliflozin was associated with only modest reductions in HbA1c (0.3 percentage points) and blood pressure (3 mm Hg systolic, 1 mm Hg diastolic). Incidence of amputation — an adverse outcome noted in other studies (NEJM JW Gen Med Sep 15 2018 and JAMA Intern Med 2018; 178:1190) — was not higher with canagliflozin in this study.

Comment: Based on this positive study, canagliflozin likely will be approved for renoprotection in type 2 diabetic patients with proteinuria. The number needed to treat for 2.5 years to prevent 1 case of progression to ESRD was roughly 42. However, note that the average cash cost of this drug in the U.S. remains very high — roughly US$7,000 per year.


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 Angela is a 2018-2019 NEJM editorial fellow. She is an endocrine fellow who trained at Flinders Medical Centre and the Royal Adelaide Hospital. Angela recieved her medical degree from the University of Adelaide, and masters of public health from the University of Sydney. Her clinical and research interests are in the areas of glucocorticoid and cardiovascular endocrinology and diabetes medicine.