Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes

Abstract

Background: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease.

Methods: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m² of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed.

Results: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m² in the allopurinol group and 67.3 ml per minute per 1.73 m² in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m² (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m² per year with allopurinol and -2.5 ml per minute per 1.73 m² per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m² per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups.

Conclusions: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).

Figure 1.. Serum Urate and Iohexol-based Glomerular Filtration Rate (GFR) Trajectories.

The mean levels of serum urate (Panel A) and the mean iohexol-based GFR (Panel B) in the two groups are shown at different time points during the trial. I bars indicate 95% confidence intervals. The mean serum urate values are shown for participants with available levels at each time point. The mean iohexol-based GFR values are shown for the entire intention-to-treat population, with missing values imputed as described in the Methods section. The intervention period ended at week 156 after randomization, and the 2-month washout period ended at week 164. To convert the values for serum urate to micromoles per liter, multiply by 59.48.

Figure 2.. Prespecified Subgroup Analyses of the Effect of Allopurinol on the Primary Outcome.

The mean differences in the primary outcome (the iohexol-based GFR at the end of the 2-month washout period) between the allopurinol group and the placebo group are shown in prespecified subgroups. Positive values denote a higher iohexol-based GFR in the allopurinol group than in the placebo group (i.e., benefit with allopurinol); negative values denote a lower iohexol-based GFR in the allopurinol group than in the placebo group (i.e., harm with allopurinol). Race was reported by the patient.