Sustained serum urate reduction with allopurinol may not improve kidney outcomes in patients with type 1 diabetes and mild-to-moderate diabetic kidney disease, a double-blind randomized controlled trial found.
At multiple study sites, researchers randomly assigned 530 participants (mean age, 51.1 years; 66.2% men; 84.2% white) with type 1 diabetes, a serum urate level of at least 4.5 mg/dL, an estimated glomerular filtration rate (GFR) of 40.0 to 99.9 mL/min/1.73 m2 of body surface area, and evidence of diabetic kidney disease to receive allopurinol (starting dose, 100 mg/d) or placebo. Most patients in both groups were also treated with renin-angiotensin system inhibitors. The primary outcome was baseline-adjusted GFR, as measured with iohexol, after three years plus a two-month washout period. Results were published on June 25 by the New England Journal of Medicine.
Two hundred sixty-seven patients were assigned to receive allopurinol, and 263 were assigned to receive placebo. On average, participants' duration of diabetes was 34.6 years, and HbA1c level was 8.2%. Mean baseline iohexol-based GFR was 68.7 mL/min/1.73 m2 in the allopurinol group and 67.3 mL/min/1.73 m2 in the placebo group. During the intervention period, the mean serum urate level decreased by 36% with allopurinol (from 6.1 to 3.9 mg/dL) and remained at 6.1 mg/dL with placebo. After the washout period, both groups had a mean iohexol-based GFR of 61.2 mL/min/1.73 m2, with a between-group difference of 0.001 mL/min/1.73 m2 (95% CI, −1.9 to 1.9; P=0.99). There was also no evidence of benefit of allopurinol with regard to secondary outcomes, including iohexol-based GFR at the end of the intervention period. The frequency of serious adverse events was similar in the two groups, as were the percentages of patients who discontinued allopurinol or placebo because of such events.
Among other limitations, data on the primary outcome were missing and were imputed in about 20% of trial participants, and a trial of longer duration might be necessary to reveal differences between groups, the study authors noted. It was also not possible to test the effect of allopurinol therapy in the absence of renin-angiotensin system inhibitors, which represent the standard of care, they said.
Findings indicate that allopurinol is not indicated for chronic kidney disease control in middle-aged patients with diabetic nephropathy, although the trial did not address urate-lowering therapy in younger patients, an accompanying editorial noted. “As is often the conclusion in clinical research, more high-quality randomized, controlled trials are needed,” the editorialist wrote.