Renal side effects of diabetes drugs were in the news in the past month, with one industry-funded study finding an association between empagliflozin and slower progression of kidney disease and the FDA strengthening an existing warning on risk of acute kidney injury with canagliflozin and dapagliflozin.
The study, which was published on June 14 by the New England Journal of Medicine, reported on a subanalysis of the EMPA-REG OUTCOME trial, in which patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 mg/min/1.73 m2 were randomly assigned to receive empagliflozin, 10 mg or 25 mg, or placebo once daily. The trial was funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. A prespecified secondary objective of the trial was to examine the long-term renal effects of empagliflozin in patients with type 2 diabetes who were at high cardiovascular risk. Incident or worsening nephropathy and incident albuminuria were the prespecified renal outcomes.
Of 4,124 patients assigned to the empagliflozin group and 2,061 assigned to the placebo group, 525 (12.7%) and 388 (18.8%), respectively, developed incident or worsening nephropathy. The hazard ratio in the empagliflozin group was 0.61 (95% CI, 0.53 to 0.70; P<0.001). Serum creatinine level doubled in 70 of 4,645 patients (1.5%) in the empagliflozin group and 60 of 2,323 patients (2.6%) in the placebo group, while renal replacement therapy was started in 13 of 4,687 patients (0.3%) versus 14 of 2,333 patients (0.6%) in each group, respectively. Rate of incident albuminuria did not differ significantly between groups.
The authors noted that their findings cannot be generalized to diabetic patients who are at lower risk for cardiovascular events or to black patients and called for additional research to validate their findings in larger populations. However, they concluded that in their study sample of patients with type 2 diabetes at high cardiovascular risk, empagliflozin therapy added to standard care was associated with slower progression to kidney disease versus placebo, as well as a lower risk for “clinically relevant renal events.”
Also on June 14, the FDA announced in a safety alert that it had strengthened its existing warning about risk for acute kidney injury associated with canagliflozin and dapagliflozin and had added recommendations to the drug labeling to reduce this risk. The FDA recommended that health care professionals consider factors that could predispose patients to acute kidney injury, such as chronic renal insufficiency, congestive heart failure, and use of medications such as diuretics or NSAIDs; assess renal function before therapy; and monitor renal function periodically afterward. Canagliflozin and dapagliflozin should be promptly discontinued if acute kidney injury occurs during therapy, the FDA said.